Benzothiophene-based selective estrogen receptor downregulators

ABSTRACT

This invention is benzothiophene-based estrogen receptor downregulators and their compositions and uses to treat estrogen-related medical disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/537,079, filed Aug. 9, 2019, which is a continuation of Ser. No.16/169,812, filed Oct. 24, 2018, which is a divisional of U.S. patentapplication Ser. No. 15/374,966, filed Dec. 9, 2016, which claims thebenefit of U.S. Provisional Application 62/322,878 filed Apr. 15, 2016and which claims the benefit of U.S. Provisional Application 62/264,971filed Dec. 9, 2015. The entirety of these applications is herebyincorporated by reference for all purposes.

STATEMENT OF GOVERNMENTAL INTEREST

This invention was made with government support under contract no.1R01CA188017-01A1 awarded by the National Institutes of Health. Thegovernment has certain rights in this invention.

TECHNICAL FIELD

This invention provides compounds and compositions that includebenzothiophene-based estrogen receptor ligands and uses of thesecompounds to treat estrogen-related medical disorders.

BACKGROUND OF THE INVENTION

Estrogens are the primary female hormones responsible for thedevelopment and regulation of the female reproductive system andsecondary female sex characteristics. Estrogens also have pleotropicroles in protein synthesis, coagulation, lipid balance, fluid balance,melanin, gastrointestinal track function, lung function, cognition,immune response and heart disease, among others.

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of the variety of biologicaleffects through its interaction with endogenous estrogens, including17β-estradiol and estrones. ER has been found to have two isoforms, ER-αand ER-β, and both receptors are involved in the regulation anddevelopment of the female reproductive tract.

ERs and estrogens regulate biological processes through several distinctpathways. The classical pathway involves the binding of aligand-activated ER to a specific DNA sequence motif called an estrogenresponse element (ERE). ERs can also participate in non-classicalpathways such as ERE-independent gene transcription via protein-proteininteractions with other transcription factors, non-genomic pathways withrapid effects, and ligand-independent pathways that involve activationthrough other signaling pathways. This ER signaling is not only crucialfor the development and maintenance of female reproductive organs, butalso for bone metabolism and mass, lipid metabolism, cardiovascularprotection, and central nervous system signaling.

Research in this area has confirmed the enormous complexity of estrogenand ER activities. A goal of drug development has been to create newcompounds that modulate estrogen activity, either by acting as anantagonist or an agonist, or a partial antagonist or partial agonist.

One goal has been to identify complete anti-estrogens (completeantagonists) that have the effect of shutting down all estrogenicactivity in the body. Fulvestrant is an example of a complete estrogenreceptor antagonist with no agonist activity. It is a selective estrogenreceptor downregulator (SERD). Fulvestrant was disclosed by ImperialChemical Industries (ICI) in U.S. Pat. No. 4,659,516 and is sold byAstraZeneca under the name Faslodex. It is indicated for the treatmentof hormone receptor positive metastatic breast cancer in post-menopausalwomen with disease progression following anti-estrogen therapy.Fulvestrant has limited water solubility and requires monthlyintramuscular (IM) injections. Fulvestrant's aqueous insolubilitycreates a challenge to achieve and maintain efficacious serumconcentrations.

Another class of anti-estrogens are selective estrogen receptormodulators (SERMs) which act as antagonists or agonists in agene-specific and tissue-specific fashion. A goal of SERM therapy is toidentify drugs with mixed profiles that afford beneficial targetanti-estrogenic activity and either avoid adverse off-target effects orexhibit incidental beneficial estrogenic side effects. An example of aSERM is tamoxifen, initially sold by AstraZeneca under the nameNolvadex. Tamoxifen was also disclosed by ICI in U.S. Pat. No.4,659,516, (see also U.S. Pat. Nos. 6,774,122 and 7,456,160). Tamoxifenis a prodrug that is metabolized to 4-hydroxytamoxifen andN-desmethyl-4-hydroxytamoxifen which have high binding affinity to theestrogen receptor. Tamoxifen is indicated to prevent further breastcancer after breast cancer treatment and to treat node-positive breastcancer in women following mastectomy and radiation. Tamoxifen can affectbone health. In pre-menopausal women, tamoxifen can cause bone thinning,while it can be beneficial for bone health in post-menopausal woman.Serious side effects have been noted, including increased risk ofuterine cancer in post-menopausal women and “tumor flares” in women withbreast cancer that has spread to the bone. In addition to these sideeffects, some women who initially respond to tamoxifen experienceacquired resistance over time, and in some cases ER positive breastcancer not only becomes resistant to tamoxifen, but tamoxifen becomes anagonist which induces tumor proliferation.

A third line of treatment for breast cancer includes steroidal andnon-steroidal aromatase inhibitors that block the production of estrogenand therefore block ER-dependent growth. These drugs, which includeletrozole, anastrozole, and exemestane, have the risk of removing allestrogens from women after menopause, increasing the risk of bonethinning, osteoporosis, and fractures.

A number of SERDs, SERMs, and aromatase inhibitors have been disclosed.The SERM raloxifene was disclosed by Eli Lilly in 1981 (U.S. Pat. Nos.4,418,068; 5,478,847; 5,393,763; and 5,457,117) for prevention of breastcancer and treatment of osteoporosis. In June 2011, AragonPharmaceuticals disclosed benzopyran derivatives and acolbifene analogsfor treatment of tamoxifen-resistant breast cancer (see WO2011/156518,U.S. Pat. Nos. 8,455,534 and 8,299,112). Aragon became Seragon in 2013,and was purchased by Genentech in 2014. See also U.S. Pat. Nos.9,078,871; 8,853,423; 8,703,810; US 2015/0005286; and WO 2014/205138.Genentech is now developing Brilanstrant (GDC-0810, formerly ARN-810)for the treatment of locally advanced or metastatic estrogenic receptorpositive breast cancer.

Genentech disclosed a series of tetrahydro-pyrido[3,4-b]indol-1-ylcompounds with estrogen receptor modulation activity in US2016/0175289and a combination therapy of three compounds, one of which was GDN-0810,for estrogen receptor modulation in US2015/0258080.

AstraZeneca is currently developing AZD9496, a novel, oral selectiveestrogen receptor downregulator in patients with estrogen receptorpositive breast cancer (WO 2014/191726).

Additional anti-estrogenic compounds are disclosed in WO 2012/084711; WO2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; U.S. Pat.No. 6,821,989; US 2002/0128276; U.S. Pat. No. 6,777,424; US2002/0016340; U.S. Pat. Nos. 6,326,392; 6,756,401; US 2002/0013327; U.S.Pat. Nos. 6,512,002; 6,632,834; US 2001/0056099; U.S. Pat. Nos.6,583,170; 6,479,535; WO 1999/024027; U.S. Pat. No. 6,005,102; EP0802184; U.S. Pat. Nos. 5,998,402; 5,780,497 and 5,880,137.

J-Pharma is currently developing benzothiophene compounds for thetreatment of disorders related to urate transportation. See for exampleWO 2012/048058.

Bionomics LTD is developing benzofurans, benzothiophenes,benzoselenophenes, and indoles for treatment of tubulin polymerizationrelated disorders. See for example WO 2007/087684.

Additional benzothiophene compounds are disclosed in WO 2010/127452, WO2010/093578, WO 2009/013195, EP1947085, JP 2005-129430, US 2007/0112009,WO 2005/016929, EP0752421, EP0622673, EP0551849, EP0545478, U.S. Pat.No. 5,491,123, and WO 2006/084338.

Given the often devastating effects of estrogen-modulated disorders,including cancer, tumors, and in particular breast cancer, there remainsa strong need to create new drugs that have significant anti-estrogenicefficacy without unacceptable side effects.

SUMMARY OF THE INVENTION

Benzothiophene compounds and their pharmaceutically acceptable salts areprovided that have advantageous selective estrogen receptor modulatingactivity, and in particular, anti-estrogenic activity. The compounds canbe used for the treatment of a patient, typically a human, with anestrogen-related medical disorder, including but not limited to a canceror a tumor by administering an effective amount to the patient in needthereof, optionally in a pharmaceutically acceptable carrier. In certainembodiments, the cancer is selected from breast, ovarian, endometrial,kidney, and uterine. In another embodiment the cancer is metastaticendocrine therapy resistant breast cancer. Alternatively, a compound orits pharmaceutically acceptable salt can be used to prevent anestrogen-mediated disorder, including but not limited to a cancer or atumor, including breast, ovarian, endometrial, kidney, and uterinecancer. In some embodiments, the compound is used following chemotherapyor radiation treatment to avoid recurrence, or instead of chemotherapyor radiation as a primary treatment.

In one embodiment, a compound of the present invention is a selectiveestrogen downregulator (SERD). In another embodiment, a compound of thepresent invention can be a selective mixed estrogen receptordownregulator (SMERD). In one embodiment the compound antagonizes E₂ inbreast epithelial cells and causes significant degradation of ERα.

In one aspect, a compound of the present invention or itspharmaceutically acceptable salt or prodrug, can be used to treat ahormone-related cancer or tumor that has metastasized to the brain, boneor other organ. In one embodiment of this aspect, the hormone-relatedcancer is estrogen mediated. In another embodiment, the estrogenmediated cancer is selected from breast, uterine, ovarian andendometrial. In other embodiments, a compound of the present inventionor its pharmaceutically acceptable salt or prodrug, can be used toprevent a hormone-related cancer or tumor from metastasizing to thebrain, bone or other organ, including a hormone-related cancer that isestrogen mediated, for example, breast, uterine, ovarian or endometrial.

In one aspect, this invention is a compound of Formula A, or apharmaceutically acceptable salt thereof:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X_(A) is selected from —O—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, andC₃cycloalkyl;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositionthat includes a compound of Formula A and a pharmaceutically acceptablecarrier or excipient.

In another aspect, this invention is a method to treat or prevent atumor or cancer that includes administering to a subject, typically ahuman, in need of such treatment, a therapeutically effective amount ofa compound of Formula A or a pharmaceutically acceptable salt thereof.

In another aspect, this invention is a compound of Formula B, or apharmaceutically acceptable salt thereof:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X_(B) is selected from —O—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Y is selected from —C(O)—, —O—, —CF₂—, or —C₃cycloalkyl-, —CH₂—, —S—,—NH—, and —N(Me)-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositionthat includes a compound of Formula B and a pharmaceutically acceptablecarrier or excipient.

In another aspect, this invention is a method to treat or prevent atumor or cancer that includes administering to a subject such as a humanin need of such treatment a therapeutically effective amount of acompound of Formula B or a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides a compound of Formula C:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X is selected from —O—, —C(O)—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Y is selected from —C(O)—, —O—, —CF₂—, or —C₃cycloalkyl-, —CH₂—, —S—,—NH—, and —N(Me)-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl, cycloalkyl, or 7-, 8-, 9- or 10 membered bicyclicheterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R_(2C) is selected from —CH═CHCOOH, —NH(CO)COOH, -cycloalkyl(COOH),—C₂-C₆alkenylene-COOH, and —C₂-C₆alkynylene-COOH.

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositionthat includes one or more compounds of Formula C and a pharmaceuticallyacceptable carrier or excipient.

In another aspect, this invention is a method to treat or prevent atumor or cancer that includes administering to a subject such as a humanin need of such treatment a therapeutically effective amount of acompound of Formula C or a pharmaceutically acceptable salt thereof.

In one aspect, this invention is a compound of Formula D, or apharmaceutically acceptable salt thereof:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X is selected from —O—, —C(O)—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Y is selected from —C(O)—, —O—, —CF₂—, or —C₃cycloalkyl-, —CH₂—, —S—,—NH—, and —NMe-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH, C₂-C₆alkenylene-COOHand C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositionthat includes one or more compounds of Formula D and a pharmaceuticallyacceptable carrier or excipient.

In another aspect, this invention is a method to treat or prevent canceror a tumor that includes administering to a subject such as a human inneed of such treatment a therapeutically effective amount of a compoundof Formula D or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound has the structure selected from, oris a pharmaceutically acceptable salt thereof:

In other embodiments, the compound is selected from the following, or isa pharmaceutically acceptable salt thereof:

In certain embodiments of the above structures that have a —CO₂H, thecompound can be presented, for example, as an ester, amide, or etherprodrug. The ester may be, for example, —CO₂R, wherein R is alkyl(including cycloalkyl), heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclic, or any other moiety that is metabolized in vivo to providethe parent drug.

The present invention includes at least the following features:

(a) a compound as described herein, or a pharmaceutically acceptablesalt or prodrug thereof;

(b) a compound as described herein, or a pharmaceutically acceptablesalt or prodrug thereof that is useful in the treatment or prevention ofan estrogen-related disorder, including without limitation a tumor orcancer;

(c) use of a compound as described herein, or a pharmaceuticallyacceptable salt or prodrug thereof in the manufacture of a medicamentfor the treatment or prevention of an estrogen-related disorder,including but not limited to a tumor or cancer;

(d) a method for manufacturing a medicament for the therapeutic use totreat or prevent a disorder of abnormal cellular proliferation includingbut not limited to a tumor or cancer, characterized in that a compoundof the present invention or its salt or prodrug as described herein isused in the manufacture;

(e) a compound as described herein or its pharmaceutically acceptablesalt or prodrug for use in the treatment or prevention of breast,kidney, uterine, ovarian or endometrial cancer;

(f) use of a compound as described herein or a pharmaceuticallyacceptable salt or prodrug thereof in the manufacture of a medicamentfor the treatment or prevention of breast, kidney, uterine, ovarian orendometrial cancer;

(g) a method for manufacturing a medicament for the therapeutic use intreating or preventing breast, kidney, uterine, ovarian or endometrialcancer, characterized in that a compound as described herein or itspharmaceutically acceptable salt or prodrug is used in the manufacture;

(h) a compound as described herein or a pharmaceutically acceptable saltor prodrug thereof for use in the treatment or prevention of hormonereceptor positive metastatic breast cancer;

(i) use of a compound as described herein or a pharmaceuticallyacceptable salt or prodrug thereof in the manufacture of a medicamentfor the treatment or prevention of a hormone receptor positivemetastatic breast cancer tumor;

(j) a method for manufacturing a medicament for treatment or preventionof a hormone receptor positive metastatic breast cancer, characterizedin that a compound as described herein or its pharmaceuticallyacceptable salt or prodrug is used in the manufacture;

(k) a compound as described herein or a pharmaceutically acceptable saltor prodrug thereof for use to treat or prevent bone loss, includingosteoporosis;

(l) use of a compound as described herein or a pharmaceuticallyacceptable salt or prodrug thereof in the manufacture of a medicamentfor the treatment or prevention of bone loss, including osteoporosis;

(m) a method for manufacturing a medicament for use to treat or preventbone loss, including osteoporosis, characterized in that a compound asdescribed herein is used in the manufacture;

(n) a pharmaceutical formulation comprising an effective treatment orprevention amount of a compound of a compound as described herein or apharmaceutically acceptable salt or prodrug thereof together with apharmaceutically acceptable carrier or diluent;

(o) a compound as described herein, or its pharmaceutically acceptablesalt or prodrug as a mixture of enantiomers or diastereomers (asrelevant), including as a racemate;

(p) a compound of the present invention as described herein inenantiomerically or diastereomerically (as relevant) enriched form,including as an isolated enantiomer or disastereomer (i.e., greater than85, 90, 95, 97 or 99% pure); and,

(q) a process for the preparation of a therapeutic product that containan effective amount of a compound as described herein, or itspharmaceutically acceptable salt or prodrug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A, FIG. 1B, FIG. 1C, FIG. 1D, and FIG. 1E are graphs of theefficacy of Compounds 1, 5, 11, and 12 compared to known compoundGDN-0810 against tamoxifen-resistant MCF-7:5C cells. The y-axis isnormalized DNA content in percent and the x-axis is the concentration ofcompound measured in log(molar) units. The graph shows thatrepresentative compounds have sub-nanomolar efficacy intamoxifen-resistant MCF-7:5C cells using DNA content assay.

FIG. 2A, FIG. 2B, FIG. 2C, and FIG. 2D are graphs of the efficacy ofCompounds 11, 12, and 13 compared to known compound GDN-0810 againsttamoxifen-resistant MCF-7:WS8 cells. The y-axis is normalized DNAcontent in percent and the x-axis is the concentration of compoundmeasured in log(molar) units. The graph shows that representativecompounds have sub-nanomolar efficacy in tamoxifen-resistant MCF-7:WS8cells using DNA content assay.

FIG. 3 is a graph of the efficacy of Compounds 11 and 12 compared toknown compound GDN-0810 GDN-0810 GDN-0810 GDN-0810 and prostaglandin E2against MCF-7:ws8, T47D:A18, and T47D:A18-TAM1 tamoxifen resistantspheroid cells. The y-axis is normalized spheroid cell population where1 is the population exposed to 100 nM DMSO (the control) and the x-axisis compound dosed at 100 nM concentrations. The graph shows thatrepresentative compounds of the invention have efficacy at 100 nM inmultiple tamoxifen resistant and sensitive 3D cells.

FIG. 4 is a western blot analysis that shows the estrogen receptordownregulation at 10 nM concentrations of Compounds 1, 3, 4, 5, 6, and 7compared to the known compounds GDN-0810 and Raloxifene. The westernblot shows that Compound 1, 3, 4, 5, 6, and 7 all downregulate theestrogen receptor at 10 nM concentrations.

FIG. 5A is a graph demonstrating the cell viability of treatmentresistance MCF-7:5C breast cancer cells. The y-axis is cell survivalmeasured in percent and normalized to baseline measurements and thex-axis is concentration of GDN-0810 or Compound 21 measured inlog(molar) units. The measurements were taken 4 days after treatment andnormalized to 100% vehicle dosing.

FIG. 5B is a graph demonstrating the cell viability of treatmentsensitive MCF-7:WS8 breast cancer cells. The y-axis is cell survivalmeasured in percent and normalized to baseline measurements and thex-axis is concentration of GDN-0810 or Compound 21 measured inlog(molar) units. The measurements were taken 4 days after treatment andnormalized to 100% vehicle dosing.

FIG. 5C is a graph demonstrating the level of estrogen receptordownregulation measured in western blot experiments. The y-axis isestrogen receptor expression level measured in percent and normalized tobaseline measurements and the x-axis is concentration of GDN-0810 orCompound 21 measured in log(molar) units. Data was normalized to 1 μMGDN-0810 as 0% and DMSO control as 100%.

FIG. 5D is a graph demonstrating the level of estrogen receptorantagonism measured in an ERE luciferase assay in MCF-7:WS8 cells. They-axis is ERE luciferase level measured in percent and normalized tobaseline measurements and the x-axis is concentration of GDN-0810 orCompound 21 measured in log(molar) units. Data was normalized to 1 μMGDN-0810 as 0% and 0.1 nM E2 as 100%. Data show mean and s.e.m. from atleast 3 cell passages.

FIG. 6 is cell microscopy images showing that SERDs inhibit growth ofMCF-7:TAM1 spheroids after 10 days of treatment. Image A is spheroids inDMSO. Image B is spheroids in the presence of 1 nM concentration ofGDN-0810. Image C is spheroids in the presence of 1 nM concentration ofCompound 21. Image D is spheroids in the presence of 10 nM concentrationof Compound 21.

FIG. 7A is a graph of tumor area using MCF7:TAM1 tumors that were grownto an average section area of 0.32 cm². The y-axis is tumor areameasured in cm² and the x-axis is time measured in weeks. For the study,mice were randomized into six treatment groups: control, tamoxifen (100mg/kg), GDN-0810 (100 mg/kg), Compound 12 (10 mg/kg), and two doses ofCompound 21 (30 mg/kg and 100 mg/kg). Compounds were administrated byoral gavage daily.

FIG. 7B is a graph of tumor area using MCF7:TAM1 tumors that were grownto an average section area of 0.32 cm². The y-axis is change in tumorarea measured as percent change at day 23 and the x-axis is compoundidentity. For the study, mice were randomized into six treatment groups:control, tamoxifen (100 mg/kg), GDN-0810 (100 mg/kg), Compound 12 (10mg/kg), and two doses of Compound 21 (30 mg/kg and 100 mg/kg). Compoundswere administrated by oral gavage daily.

FIG. 8A, FIG. 8B, and FIG. 8C are docketing images of Compounds 4, 5,and 21. Compound 4 (A), 5 (B), and 21 (C) were docked to ER LBD (pdb ID:5ak2). Compound 4 has minimum contacts with hydrophobic pockets (closeto Phe 425 and Leu 384), while compound 5 and 21 have methyl groups thattightly fit into the hydrophobic cavity and correspond to better potencyin cell viability assays.

FIG. 9 is the docked pose of Compound 4 docked to ERα LBD (pdb ID:1R₅K), showing similar global topology compared to the GW5638-ERcomplex. The acrylate side chain interaction with helix 12 is a keystructural feature of SERD-ER complexes.

FIG. 10 is the docked pose of Compound 4 docked to ERα LBD (pdb ID:1R₅K). Residues within 5 Å of Compound 12 are highlighted and twohydrophobic cavities in the vicinity of Leu384 and Phe 425 are circled.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following terms and expressions used herein have the indicatedmeanings.

Terms used herein may be preceded and/or followed by a single dash, “—”,or a double dash, “═”, to indicate the bond order of the bond betweenthe named substituent and its parent moiety; a single dash indicates asingle bond and a double dash indicates a double bond. In the absence ofa single or double dash it is understood that a single bond is formedbetween the substituent and its parent moiety; further, substituents areintended to be read “left to right” unless a dash indicates otherwise.For example, C₁-C₆alkoxycarbonyloxy and —OC(O)C₁-C₆ alkyl indicate thesame functionality; similarly, arylalkyl and -alkylaryl indicate thesame functionality.

“Alkenyl” means a straight or branched chain hydrocarbon containing from2 to 10 carbons, unless otherwise specified, and containing at least onecarbon-carbon double bond. Representative examples of alkenyl include,but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl,3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl,3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

“Alkoxy” means an alkyl group, as defined herein, appended to the parentmolecular moiety through an oxygen atom. Representative examples ofalkoxy include, but are not limited to, methoxy, ethoxy, propoxy,2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

“Alkyl” means a straight or branched chain hydrocarbon containing from 1to 10 carbon atoms unless otherwise specified. Representative examplesof alkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an“alkyl” group is a linking group between two other moieties, then it mayalso be a straight or branched chain; examples include, but are notlimited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—, and —CH₂CH(CH₂CH₃)CH₂—.

“Alkynyl” means a straight or branched chain hydrocarbon groupcontaining from 2 to 10 carbon atoms and containing at least onecarbon-carbon triple bond. Representative examples of alkynyl include,but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

“Aryl” means a phenyl (i.e., monocyclic aryl), or a bicyclic ring systemcontaining at least one phenyl ring or an aromatic bicyclic ringcontaining only carbon atoms in the aromatic bicyclic ring system. Thebicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to amonocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclicheterocyclyl. The bicyclic aryl is attached to the parent molecularmoiety through any carbon atom contained within the phenyl portion ofthe bicyclic system, or any carbon atom with the napthyl or azulenylring. The fused monocyclic cycloalkyl or monocyclic heterocyclylportions of the bicyclic aryl are optionally substituted with one or twooxo and/or thia groups. Representative examples of the bicyclic arylsinclude, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl,dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl,2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl,2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl,dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl,dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl,2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl,benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl,2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl,2,3-dihydrobenzo[b][1,4]dioxan-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-5-yl,2H-benzo[b][1,4]oxazin3(4H)-on-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia. In certainembodiments of the disclosure, the aryl group is phenyl or naphthyl. Incertain other embodiments, the aryl group is phenyl.

“Cyano” and “nitrile” mean a —CN group.

“Halo” or “halogen” means —Cl, —Br, —I or —F. In certain embodiments,“halo” or “halogen” refers to —Cl or —F.

“Haloalkyl” means at least one halogen, as defined herein, appended tothe parent molecular moiety through an alkyl group, as defined herein.Representative examples of haloalkyl include, but are not limited to,chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl. In certain embodiments, each “haloalkyl” is afluoroalkyl, for example, a polyfluoroalkyl such as a substantiallyperfluorinated alkyl.

“Heteroaryl” means a monocyclic heteroaryl or a bicyclic ring systemcontaining at least one heteroaromatic ring. The monocyclic heteroarylcan be a 5 or 6 membered ring. The 5 membered ring consists of twodouble bonds and one, two, three or four nitrogen atoms and optionallyone oxygen or sulfur atom. The 6 membered ring consists of three doublebonds and one, two, three or four nitrogen atoms. The 5 or 6 memberedheteroaryl is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the heteroaryl.Representative examples of monocyclic heteroaryl include, but are notlimited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, andtriazinyl. The bicyclic heteroaryl consists of a monocyclic heteroarylfused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, amonocyclic heterocyclyl, or a monocyclic heteroaryl. The fusedcycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group isoptionally substituted with one or two groups which are independentlyoxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl,cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl groupis connected to the parent molecular moiety through any carbon ornitrogen atom contained within the monocyclic heteroaryl portion of thebicyclic ring system. When the bicyclic heteroaryl is a monocyclicheteroaryl fused to a phenyl ring, then the bicyclic heteroaryl group isconnected to the parent molecular moiety through any carbon atom ornitrogen atom within the bicyclic ring system. Representative examplesof bicyclic heteroaryl include, but are not limited to, benzimidazolyl,benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl,benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl,5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl,isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments of the disclosure, the heteroarylgroup is furyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, thiazolyl, thienyl, triazolyl, benzimidazolyl,benzofuranyl, indazolyl, indolyl, or quinolinyl.

“Heterocyclyl” means a monocyclic heterocycle or a bicyclic heterocycle.The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containingat least one heteroatom independently selected from the group consistingof 0, N, and S where the ring is saturated or unsaturated, but notaromatic. The 3 or 4 membered ring contains 1 heteroatom selected fromthe group consisting of O, N and S. The 5 membered ring can contain zeroor one double bond and one, two or three heteroatoms selected from thegroup consisting of O, N and S. The 6 or 7 membered ring contains zero,one or two double bonds and one, two or three heteroatoms selected fromthe group consisting of O, N and S. The monocyclic heterocycle isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the monocyclic heterocycle.Representative examples of monocyclic heterocycle include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to either a phenyl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocycle, or a monocyclic heteroaryl. The bicyclic heterocycle isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the monocyclic heterocycle portion of thebicyclic ring system. Representative examples of bicyclic heterocyclylsinclude, but are not limited to, 2,3-dihydrobenzofuran-2-yl,2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl,2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl,octahydro-1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl isoptionally substituted by one or two groups which are independently oxoor thia. In certain embodiments of the disclosure, the heterocyclyl ispyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

“Saturated” means the referenced chemical structure does not contain anymultiple carbon-carbon bonds. For example, a saturated cycloalkyl groupas defined herein includes cyclohexyl, cyclopropyl, and the like.

“Unsaturated” means the referenced chemical structure contains at leastone multiple carbon-carbon bond, but is not aromatic. For example, aunsaturated cycloalkyl group as defined herein includes cyclohexenyl,cyclopentenyl, cyclohexadienyl, and the like.

“Pharmaceutically acceptable salt” refers to both acid and base additionsalts. “Modulating” or “modulate” refers to the treating, prevention,suppression, enhancement or induction of a function, condition ordisorder.

“Treating” or “treatment” refer to the treatment of a disease ordisorder described herein, in a subject, preferably a human, andincludes:

i. inhibiting a disease or disorder, i.e., arresting its development;

ii. relieving a disease or disorder, i.e., causing regression of thedisorder;

iii. slowing progression of the disorder; and/or

iv. inhibiting, relieving, or slowing progression of one or moresymptoms of the disease or disorder.

“Subject” refers to a warm blooded animal such as a mammal, preferably ahuman, or a human child, which is afflicted with, or has the potentialto be afflicted with one or more diseases and disorders describedherein.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means any of the presently described chemical compoundsdescribed herein. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Nonlimitingexamples of prodrugs include those with covalent attachment of removablegroups, or removable portions of groups, for example, but not limited toacylation, phosphorylation, phosphonylation, phosphoramidatederivatives, amidation, reduction, oxidation, esterification,alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives,carbonylation or anhydride, among others.

The materials, compounds, compositions, articles, and methods describedherein may be understood more readily by reference to the followingdetailed description of specific aspects of the disclosed subject matterand the Examples and Figures. It is to be understood that the aspectsdescribed below are not limited to specific embodiments which may, ofcourse, vary, as known to those skilled in the art. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

Compounds

Benzothiophene based estrogen receptor ligands of the invention includescompounds of Formula A, or a pharmaceutically acceptable salt thereof:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X_(A) is selected from —O—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositioncomprising one or more compounds of Formula A and a pharmaceuticallyacceptable carrier or excipient.

In another aspect, this invention is a method of treating or preventingcancer (including breast, ovarian, uterine, kidney, or endometrial) or atumor that includes administering to a subject such as a human in needof such treatment a therapeutically effective amount of a compound ofFormula A or a pharmaceutically acceptable salt thereof.

In another aspect, this invention is a compound of Formula B, or apharmaceutically acceptable salt thereof:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X_(B) is selected from —O—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Y is selected from —C(O)—, —O—, —CF₂—, or —C₃cycloalkyl-, —CH₂—, —S—,—NH—, and —N(Me)-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositioncomprising one or more compounds of Formula B and a pharmaceuticallyacceptable carrier or excipient.

In another aspect, this invention is a method of treating or preventingcancer (including breast, ovarian, uterine, kidney, or endometrial) or atumor comprising administering to a subject such as a human in need ofsuch treatment a therapeutically effective amount of a compound ofFormula B or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect, this invention provides a compound of Formula C:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X is selected from —O—, —C(O)—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Y is selected from —C(O)—, —O—, —CF₂—, or C₃cycloalkyl, —CH₂—, —S—,—NH—, and —NMe-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl, cycloalkyl, or 7-, 8-, 9- or 10 membered bicyclicheterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl, cycloalkyl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R_(2C) is selected from —CH═CHCOOH, —NH(CO)COOH, —C₂-C₆alkenylene-COOHand —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositionthat includes one or more compounds of Formula C and a pharmaceuticallyacceptable carrier or excipient.

In another aspect, this invention is a method of treating or preventinga cancer (including breast, ovarian, uterine, kidney, or endometrial) ortumor that includes administering to a subject such as a human in needof such treatment a therapeutically effective amount of a compound ofFormula C or a pharmaceutically acceptable salt or prodrug thereof.

In one aspect, this invention is a compound of Formula D, or apharmaceutically acceptable salt thereof:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

X is selected from —O—, —C(O)—, —CH₂—, —S—, —NH—, —NMe-, —CF₂—, and—C₃cycloalkyl-;

Y is selected from —C(O)—, —O—, —CF₂—, or —C₃cycloalkyl, —CH₂—, —S—,—NH—, and —NMe-;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In another aspect, this invention includes a pharmaceutical compositionthat includes one or more compounds of Formula D or its pharmaceuticallyacceptable salt or prodrug and a pharmaceutically acceptable carrier orexcipient.

In another aspect, this invention is a method of treating or preventingcancer (including breast, ovarian, uterine, kidney, or endometrial) thatincludes administering to a subject in need of such treatment atherapeutically effective amount of a compound of Formula D or apharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the present invention, X is —O—.

In another embodiment, Y is —C(O)—.

In a further embodiment X is —O— and Y is —C(O)—.

In one embodiment, R₁ is selected from hydroxyl and —O(C₁-C₆ alkyl).

In one embodiment, R₂ is selected from —COOH, —NH(CO)COOH and—CH═CHCOOH.

In one embodiment, Ring B is phenyl, naphthyl or quinolinyl and Ring Cis phenyl or thienyl.

In one embodiment, Ring C is phenyl.

In one embodiment,

is selected from:

In one embodiment of the above B-ring embodiments, alkyl is methyl. Inanother embodiment of the above B-ring embodiments, alkyl isindependently, methyl, ethyl, propyl or cyclopropyl. In one embodimentof the above B-ring embodiments, halo is fluoro. In another embodimentof the above B-rings, halo is independently fluoro or chloro, includingwherein one halo is fluoro and the other is chloro. In one embodiment ofthe above B-ring embodiments, haloalkyl is independently mono-, di- ortrifluoro-methyl.

In another embodiment,

is selected from:

In one embodiment,

is selected from:

In one embodiment of the above C-ring embodiments, alkyl is methyl. Inanother embodiment of the above C-ring embodiments, alkyl isindependently, methyl, ethyl, propyl or cyclopropyl. In one embodimentof the above C-ring embodiments, halo is fluoro. In another embodimentof the above C-rings, halo is independently fluoro or chloro, includingwherein one halo is fluoro and the other is chloro. In one embodiment ofthe above B-ring embodiments, haloalkyl is independently mono-, di- ortrifluoro-methyl.

In another embodiment,

is selected from:

In one embodiment of the above C-ring embodiments, R₄ is hydrogen. Inanother embodiment, R₄ is —C₁-C₆alkyl, such as methyl, ethyl, or propyl.In yet another embodiment, R₄ is —C₁-C₆fluoroalkyl, includingtrifluoromethyl, difluoromethyl, fluoromethyl, fluoroethyl, anddifluoroethyl. In other embodiments, R₄ is selected from —CN, —O(C₁-C₆alkyl), and —O(C₁-C₆fluoroalkyl).

In another embodiment, the compound is Formula E:

wherein:

n is 0, 1, 2, 3, or 4;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In one embodiment R₃ is independently selected at each occurrence fromhydrogen, halogen, methyl and —CN.

In another embodiment, the compound is Formula F:

wherein

n is 0, 1, 2, 3, or 4;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In one embodiment R₃ is independently selected at each occurrence fromhydrogen, halogen, methyl and —CN; and

In another embodiment, the compound is Formula G:

wherein:

Z is CH or N;

n is 0, 1, 2, 3, or 4; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl) and—O(C₁-C₆fluoroalkyl).

In another embodiment, the compound is Formula H:

wherein:

n is 0, 1, 2, 3, or 4;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In one embodiment R₃ is independently selected at each occurrence fromhydrogen, halogen, methyl and —CN.

In another embodiment, a compound of Formula I is provided:

wherein:

Q is selected from O, S, CH₂, NH and S(O);

R₅ and R₆ are independently selected from —CN, halogen and —COOR₇;

R₃ is independently selected at each occurrence from hydrogen, halogen,methyl and —CN; and

R₇ is selected from haloalkyl, alkyl, cycloalkyl, aryl and heteroaryl.

In an additional embodiment, a compound of Formula J is provided:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In an additional embodiment, a compound of Formula K is provided:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₈ is selected from —CH═CHCOOH, —NH(CO)COOH, —C₂-C₆alkenylene-COOH and—C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In an additional embodiment, a compound of Formula L is provided:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

Ring B₂ is naphthyl, quinolinyl, or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₂ is selected from —CH═CHCOOH, —NH(CO)COOH, —COOH,—C₂-C₆alkenylene-COOH and —C₂-C₆alkynylene-COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, C₁-C₆alkyl, C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In an additional embodiment, a compound of Formula M is provided:

wherein:

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

Ring B₂ is naphthyl, quinolinyl, or 10 membered bicyclic heterocyclyl;

Ring C is phenyl, thiophenyl (i.e., thienyl), 5- or 6-memberedmonocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclicheterocyclyl;

R₁ is selected from hydroxyl, hydrogen, halogen, —O(C₁-C₆ alkyl),—OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅, —OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and—OSO₂(C₂-C₆ alkyl);

R₉ is —COOH;

R₃ is independently selected at each occurrence from hydrogen, halogen,—CN, —NO₂, —C₁-C₆alkyl and —C₁-C₆fluoroalkyl; and

R₄ is independently selected at each occurrence from hydrogen, halogen,hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl), and—O(C₁-C₆fluoroalkyl).

In one embodiment R₁ is hydroxyl.

In one embodiment the compound is selected from Formula A and R₁ ishydroxyl, halogen, or —O(C₁-C₆ alkyl).

In one embodiment the compound is selected from Formula B and R₁ ishydroxyl, halogen, or —O(C₁-C₆ alkyl).

In one embodiment the compound is selected from Formula C and R₁ ishydroxyl, halogen, or —O(C₁-C₆ alkyl).

In one embodiment the compound is selected from Formula D and R₁ ishydroxyl, halogen, or —O(C₁-C₆ alkyl).

In one embodiment R₂ is —COOH.

In one embodiment R₂ is

In one embodiment the compound is selected from Formula A and R₂ is—COOH or

In one embodiment the compound is selected from Formula B and R₂ is—COOH or

In one embodiment the compound is selected from Formula C and R₂ is—COOH or

In one embodiment the compound is selected from Formula D and R₂ is—COOH or

In one embodiment, R₃ is fluorine.

In one embodiment, R₃ is chlorine.

In one embodiment, R₃ is methyl.

In one embodiment the compound is selected from Formula A and R₃ ishalogen or —C₁-C₆alkyl, including methyl, ethyl, propyl, and iso-propyl.

In one embodiment the compound is selected from Formula B and R₃ ishalogen or —C₁-C₆alkyl, including methyl, ethyl, propyl, and iso-propyl.

In one embodiment the compound is selected from Formula C and R₃ ishalogen or —C₁-C₆alkyl, including methyl, ethyl, propyl, and iso-propyl.

In one embodiment the compound is selected from Formula D and R₃ ishalogen or —C₁-C₆alkyl, including methyl, ethyl, propyl, and iso-propyl.

In one embodiment R₄ is halogen.

In one embodiment R₄ is —C₁-C₆alkyl.

In one embodiment R₄ is hydroxyl.

In one embodiment the compound is selected from Formula A and R₄ ishalogen, —C₁-C₆alkyl, or hydroxyl.

In one embodiment the compound is selected from Formula B and R₄ ishalogen, —C₁-C₆alkyl, or hydroxyl.

In one embodiment the compound is selected from Formula C and R₄ ishalogen, —C₁-C₆alkyl, or hydroxyl.

In one embodiment the compound is selected from Formula D and R₄ ishalogen, —C₁-C₆alkyl, or hydroxyl.

In one embodiment m is 0.

In one embodiment m is 1.

In one embodiment m is 2

In one embodiment the compound is selected from Formula A and m is 0, 1,or 2.

In one embodiment the compound is selected from Formula B and m is 0, 1,or 2.

In one embodiment the compound is selected from Formula C and m is 0, 1,or 2.

In one embodiment the compound is selected from Formula D and m is 0, 1,or 2.

In one embodiment n is 0.

In one embodiment n is 1.

In one embodiment n is 2

In one embodiment the compound is selected from Formula A and n is 0, 1,or 2.

In one embodiment the compound is selected from Formula B and n is 0, 1,or 2.

In one embodiment the compound is selected from Formula C and n is 0, 1,or 2.

In one embodiment the compound is selected from Formula D and n is 0, 1,or 2.

In one embodiment X is —O—.

In one embodiment the compound is selected from Formula B and X is —O—.

In one embodiment the compound is selected from Formula C and X is —O—.

In one embodiment the compound is selected from Formula D and X is —O—.

In one embodiment Y is —CO—.

In one embodiment the compound is selected from Formula B and Y is —CO—.

In one embodiment the compound is selected from Formula C and Y is —CO—.

In one embodiment the compound is selected from Formula D and Y is —CO—.

In one embodiment Ring B is phenyl.

In one embodiment Ring B is napthyl.

In one embodiment Ring B is quinolinyl.

In one embodiment the compound is selected from Formula A and Ring B isphenyl, napthyl, or quinolinyl.

In one embodiment the compound is selected from Formula B and Ring B isphenyl, napthyl, or quinolinyl.

In one embodiment the compound is selected from Formula C and Ring B isphenyl, napthyl, or quinolinyl.

In one embodiment the compound is selected from Formula D and Ring B isphenyl, napthyl, or quinolinyl.

In one embodiment Ring C is phenyl.

In one embodiment the compound is selected from Formula A and Ring C isphenyl.

In one embodiment the compound is selected from Formula B and Ring C isphenyl.

In one embodiment the compound is selected from Formula C and Ring C isphenyl.

In one embodiment m and n are 0.

In one embodiment m is 0 and n is 1.

In one embodiment m is 0 and n is 2.

In one embodiment m is 1 and n is 0.

In one embodiment m is 1 and n is 1.

In one embodiment m is 1 and n is 2.

In one embodiment m is 2 and n is 0.

In one embodiment m is 2 and n is 1.

In one embodiment m is 2 and n is 2.

In one embodiment X is —O— and Y is —C(O)—.

In one embodiment R₁ is hydroxyl, X is —O—, and Y is —C(O).

In one embodiment R₁ is hydroxyl, X is —O—, Y is —C(O), and R₂ is

In one embodiment R₁ is hydroxyl, X is —O—, Y is —C(O), and n is 0.

In one embodiment R₁ is hydroxyl, X is —O—, Y is —C(O), and m is 0.

In one embodiment R₁ is hydroxyl, X is —O—, Y is —C(O), Ring B is phenyland R₂ is

In one embodiment R₁ is hydroxyl, X is —O—, Y is —C(O), and Ring B isnapthyl, and R₂ is —COOH.

In one embodiment R₁ is hydroxyl, X is —O—, Y is —C(O), and Ring B isquinolinyl, and R₂ is —COOH.

Non-limiting examples of compounds of the present invention include:

In certain embodiments of the above structures, alkyl is methyl. Inother embodiments of the above structures embodiments, alkyl isindependently methyl, ethyl, propyl or cyclopropyl. In some embodimentsof the above embodiments, halo is fluoro. In some embodiments, haloalkylis independently mono-, di- or trifluoro-methyl. In certain embodimentswhere the benzene ring has two halos, the halos can be one fluoro onechloro, two fluoros, or two chloros. In certain embodiments where thebenzene ring has three halos, the halos can be one fluoro two chloros,two fluoros one chloro, three fluoros, or three chloros.

Additional non-limiting examples of compounds of the present inventioninclude:

Additional non-limiting examples of compounds of the present inventioninclude:

In certain embodiments of the above structures, alkyl is methyl. Inother embodiments of the above structures embodiments, alkyl isindependently methyl, ethyl, propyl or cyclopropyl. In some embodimentsof the above embodiments, halo is fluoro. In some embodiments, haloalkylis independently mono-, di- or trifluoro-methyl. In certain embodimentswhere the benzene ring has two halos, the halos can be one fluoro onechloro, two fluoros, or two chloros. In certain embodiments where thebenzene ring has three halos, the halos can be one fluoro two chloros,two fluoros one chloro, three fluoros, or three chloros.

Additional non-limiting examples of compounds of the present inventioninclude:

In certain embodiments of the above structures, alkyl is methyl. Inother embodiments of the above structures embodiments, alkyl isindependently methyl, ethyl, propyl or cyclopropyl. In some embodimentsof the above embodiments, halo is fluoro. In some embodiments, haloalkylis independently mono-, di- or trifluoro-methyl. In certain embodimentswhere the benzene ring has two halos, the halos can be one fluoro onechloro, two fluoros, or two chloros. In certain embodiments where thebenzene ring has three halos, the halos can be one fluoro two chloros,two fluoros one chloro, three fluoros, or three chloros.

Additional non-limiting examples of compounds of the present inventioninclude:

In certain embodiment of the above structures, alkoxy is methoxy. Inother embodiments of the above structures embodiments, alkoxy is ethoxy,propoxy or cyclopropyloxy. In some embodiments, haloalkyl is mono-, di-or trifluoro-methyl.

Representative compounds of the invention include, but are not limitedto compounds of formula:

or a pharmaceutically acceptable salt or prodrug thereof.

Additional representative compounds of the invention include, but arenot limited to compounds of formula:

or a pharmaceutically acceptable salt thereof.

Additional representative compounds of the invention include, but arenot limited to compounds of formula:

or a pharmaceutically acceptable salt thereof.

Additional representative compounds of the invention include, but arenot limited to compounds of formula:

Additional representative compounds of the invention include, but arenot limited to compounds of formula:

Additional representative compounds of the invention include, but arenot limited to compounds of formula:

In one embodiment of any of the above structures that have a —CO₂H, thecompound can be presented, for example, as an ester, amide, or etherprodrug. The ester may be, for example, —CO₂R, wherein R is alkyl(including cycloalkyl), heteroalkyl, alkenyl, alkynyl, aryl, heteoraryl,heterocyclic, or any other moiety that is metabolized in vivo to providethe parent drug.

Pharmaceutical Compositions and Methods of Treatment

This invention includes pharmaceutical compositions that include atherapeutically effective amount of a compound as described herein orits pharmaceutically acceptable salt or prodrug, and one or more of apharmaceutically acceptable vehicle such as a diluent, preservative,solubilizer, emulsifier, adjuvant, excipient, or carrier. Excipientsinclude, but are not limited to, liquids such as water, saline,glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like.

The term “pharmaceutically acceptable carrier” refers to a diluent,adjuvant, excipient or carrier with which a compound of the disclosureis administered. The terms “effective amount” or “pharmaceuticallyeffective amount” refer to a nontoxic but sufficient amount of the agentto provide the desired biological result. That result can be reductionand/or alleviation of the signs, symptoms, or causes of a disease, orany other desired alteration of a biological system. An appropriate“effective” amount in any individual case can be determined by one ofordinary skill in the art using routine experimentation.“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: MackPublishing Company, 1990). For example, sterile saline andphosphate-buffered saline at physiological pH can be used.Preservatives, stabilizers, dyes and even flavoring agents can beprovided in the pharmaceutical composition. For example, sodiumbenzoate, sorbic acid and esters of p-hydroxybenzoic acid can be addedas preservatives. Id. at 1449. In addition, antioxidants and suspendingagents can be used. Id.

Suitable excipients for non-liquid formulations are also known to thoseof skill in the art. A thorough discussion of pharmaceuticallyacceptable excipients and salts is available in Remington'sPharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack PublishingCompany, 1990).

Additionally, auxiliary substances, such as wetting or emulsifyingagents, biological buffering substances, surfactants, and the like, canbe present in such vehicles. A biological buffer can be any solutionwhich is pharmacologically acceptable, and which provides theformulation with the desired pH, i.e., a pH in the physiologicallyacceptable range. Examples of buffer solutions include saline, phosphatebuffered saline, Tris buffered saline, Hank's buffered saline, and thelike.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, can include other pharmaceutical agents, adjuvants,diluents, buffers, and the like.

In general, the compositions of the disclosure will be administered in atherapeutically effective amount by any of the accepted modes ofadministration. Suitable dosage ranges depend upon numerous factors suchas the severity of the disease to be treated, the age and relativehealth of the subject, the potency of the compound used, the route andform of administration, the indication towards which the administrationis directed, and the preferences and experience of the medicalpractitioner involved. One of ordinary skill in the art of treating suchdiseases will be able, without undue experimentation and in relianceupon personal knowledge and the disclosure of this application, toascertain a therapeutically effective amount of the compositions of thedisclosure for a given disease.

Compositions for administration of the active compound include but arenot limited to those suitable for oral (including but not limited to atablet, capsule, liquid, gel formulation), topical, rectal, nasal,pulmonary, parenteral (including intramuscular, intra-arterial,intrathecal, subcutaneous and intravenous), intramuscular, intravenous,sub-cutaneous, transdermal (which may include a penetration enhancementagent), vaginal and suppository administration. Enteric coated oraltablets may also be used to enhance bioavailability of the compounds foran oral route of administration. The most effective dosage form willdepend upon the bioavailability/pharmacokinetics of the particularcompound chosen as well as the severity of disease in the patient. Oraldosage forms are particularly typical, because of ease of administrationand prospective favorable patient compliance.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,and the like, an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered can also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate, andthe like. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, referenced above.

Yet another embodiment is the use of permeation enhancer excipientsincluding polymers such as: polycations (chitosan and its quaternaryammonium derivatives, poly-L-arginine, aminated gelatin); polyanions(N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers(carboxymethyl cellulose-cysteine, polycarbophil-cysteine,chitosan-thiobutylamidine, chitosan-thioglycolic acid,chitosan-glutathione conjugates).

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule or can be an aqueous or nonaqueoussolution, suspension or syrup. Tablets and capsules are typical oraladministration forms. Tablets and capsules for oral use can include oneor more commonly used carriers such as lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. Typically, the compositions of the disclosure can be combinedwith an oral, non-toxic, pharmaceutically acceptable, inert carrier suchas lactose, starch, sucrose, glucose, methyl cellulose, magnesiumstearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol andthe like. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water, and the like and with emulsifying andsuspending agents. If desired, flavoring, coloring and/or sweeteningagents can be added as well. Other optional components for incorporationinto an oral formulation herein include, but are not limited to,preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions. Preferably,sterile injectable suspensions are formulated according to techniquesknown in the art using suitable carriers, dispersing or wetting agentsand suspending agents. The sterile injectable formulation can also be asterile injectable solution or a suspension in a acceptable nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Parenteral administration includes intraarticular, intravenous,intramuscular, intradermal, intraperitoneal, and subcutaneous routes,and include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and non-aqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. Administration via certain parenteralroutes can involve introducing the formulations of the disclosure intothe body of a patient through a needle or a catheter, propelled by asterile syringe or some other mechanical device such as an continuousinfusion system. A formulation provided by the disclosure can beadministered using a syringe, injector, pump, or any other devicerecognized in the art for parenteral administration.

Preferably, sterile injectable suspensions are formulated according totechniques known in the art using suitable carriers, dispersing orwetting agents and suspending agents. The sterile injectable formulationcan also be a sterile injectable solution or a suspension in a nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Preparations according to the disclosure for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms can also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They can be sterilized by, forexample, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Sterile injectable solutions are prepared by incorporating one or moreof the compounds of the disclosure in the required amount in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the various sterilized activeingredients into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof. Thus, for example, a parenteralcomposition suitable for administration by injection is prepared bystirring 1.5% by weight of active ingredient in 10% by volume propyleneglycol and water. The solution is made isotonic with sodium chloride andsterilized.

Alternatively, the pharmaceutical compositions of the disclosure can beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable nonirritatingexcipient which is solid at room temperature but liquid at the rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the disclosure can also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and can be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, propellants such as fluorocarbons or nitrogen, and/orother conventional solubilizing or dispersing agents.

Preferred formulations for topical drug delivery are ointments andcreams. Ointments are semisolid preparations which are typically basedon petrolatum or other petroleum derivatives. Creams containing theselected active agent, are, as known in the art, viscous liquid orsemisolid emulsions, either oil-in-water or water-in-oil. Cream basesare water-washable, and contain an oil phase, an emulsifier and anaqueous phase. The oil phase, also sometimes called the “internal”phase, is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation is generally anonionic, anionic, cationic or amphoteric surfactant. The specificointment or cream base to be used, as will be appreciated by thoseskilled in the art, is one that will provide for optimum drug delivery.As with other carriers or vehicles, an ointment base should be inert,stable, nonirritating and non-sensitizing.

Formulations for buccal administration include tablets, lozenges, gelsand the like. Alternatively, buccal administration can be effected usinga transmucosal delivery system as known to those skilled in the art. Thecompounds of the disclosure can also be delivered through the skin ormuscosal tissue using conventional transdermal drug delivery systems,i.e., transdermal “patches” wherein the agent is typically containedwithin a laminated structure that serves as a drug delivery device to beaffixed to the body surface. In such a structure, the drug compositionis typically contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated device can contain a single reservoir, orit can contain multiple reservoirs. In one embodiment, the reservoircomprises a polymeric matrix of a pharmaceutically acceptable contactadhesive material that serves to affix the system to the skin duringdrug delivery. Examples of suitable skin contact adhesive materialsinclude, but are not limited to, polyethylenes, polysiloxanes,polyisobutylenes, polyacrylates, polyurethanes, and the like.Alternatively, the drug-containing reservoir and skin contact adhesiveare present as separate and distinct layers, with the adhesiveunderlying the reservoir which, in this case, can be either a polymericmatrix as described above, or it can be a liquid or gel reservoir, orcan take some other form. The backing layer in these laminates, whichserves as the upper surface of the device, functions as the primarystructural element of the laminated structure and provides the devicewith much of its flexibility. The material selected for the backinglayer should be substantially impermeable to the active agent and anyother materials that are present.

The compositions of the disclosure can be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound may, for example generally havea small particle size, for example of the order of 5 microns or less.Such a particle size can be obtained by means known in the art, forexample by micronization. The active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide or other suitable gas. Theaerosol can conveniently also contain a surfactant such as lecithin. Thedose of drug can be controlled by a metered valve. Alternatively theactive ingredients can be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition can be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder can be administered by means of aninhaler.

A pharmaceutically or therapeutically effective amount of thecomposition should be delivered to the subject. The precise effectiveamount will vary from subject to subject and will depend upon thespecies, age, the subject's size and health, the nature and extent ofthe condition being treated, recommendations of the treating physician,and the therapeutics or combination of therapeutics selected foradministration. The effective amount for a given situation can bedetermined by routine experimentation. For purposes of the disclosure, atherapeutic amount may for example be in the range of about 0.01 mg/kgto about 250 mg/kg body weight, more preferably about 0.1 mg/kg to about10 mg/kg, in at least one dose. In some non-limiting embodiments, thedaily dosage may be from about 1 mg to 300 mg, one or more times perday, more preferably in the range of about 10 mg to 200 mg. The subjectcan be administered in as many doses as is required to reduce and/oralleviate the signs, symptoms, or causes of the disorder in question, orbring about any other desired alteration of a biological system. Whendesired, formulations can be prepared with enteric coatings adapted forsustained or controlled release administration of the active ingredient.

In some embodiments, for example, the dosage may be the amount ofcompound needed to provide a serum concentration of the active compoundof up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples of dosage formsare those with at least, or no greater than, 1, 2, 5, 10, 15, 20, 25,50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,or 750 mg of active compound, or its salt or prodrug. The pharmaceuticalcomposition may also include a molar ratio of the active compound and anadditional active agent, in a ratio that achieves the desired results.

The unit dosage form can be for example, a packaged preparationcontaining discrete quantities of preparation, such as packeted tablets,capsules, and powders in vials or ampoules. Also, the unit dosage formcan be a capsule, tablet, cachet, or lozenge itself, or it can be theappropriate number of any of these in packaged form.

The compounds and compositions of the invention may be used in methodsfor treatment or prevention of estrogen-related medical disorders, forexample, cancer. The cancer may be for example a breast cancer, auterine cancer, an ovarian cancer, endometrial, a prostate cancer, and alung cancer. Particularly, the breast cancer may be a tamoxifenresistant breast cancer or a triple negative breast cancer.

The method of treatment may prevent or reduce the risk of cancer or atumor. The method of treatment may cause partial or complete regressionof cancer or a tumor in a subject.

The method of treatment may cause partial or complete regression of atamoxifen resistant cancer or tumor. The method of treatment may causepartial or complete regression of a triple negative breast cancer.

In other embodiments, the compound or its pharmaceutically acceptablesalt or prodrug or a pharmaceutical composition thereof can be used toprevent recurrence of a cancer or tumor after treatment, as adjunctivetherapy. In one example, the compound or its pharmaceutically acceptablesalt or prodrug or a pharmaceutical composition thereof can be used toprevent further breast cancer after breast cancer treatment or to treatnode-positive breast cancer in women following mastectomy and/orradiation.

If desired, multiple doses of a compound described herein can beadministered to the subject. Alternatively, the subject can be given asingle dose of a compound described herein.

In one aspect of the invention, a compound disclosed herein can bebeneficially administered in combination with any therapeutic regimenentailing radiotherapy, chemotherapy, or other therapeutic agents. Inadditional embodiments the compounds disclosed herein can bebeneficially administered in combination with therapeutic agentstargeting auto-immune disorders.

The compound or its pharmaceutically acceptable salt or prodrug or apharmaceutical composition thereof may also be used to promote bonehealth or to prevent or treat osteopenia or osteoporosis.

The foregoing may be better understood by reference to the followingExamples, which are presented for purposes of illustration and are notintended to limit the scope of the invention.

In one embodiment “cancer” refers to an abnormal growth of cells whichtend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, uterus, lymphatic tissue (lymphoma),ovary, pancreas or other endocrine organ (thyroid), prostate, skin(melanoma or basal cell cancer) or hematological tumors (such as theleukemias and lymphomas) at any stage of the disease with or withoutmetastases.

In one embodiment, the cancer or tumor is estrogen-mediated. In analternative embodiment, the cancer or tumor is not estrogen-mediated. Invariable embodiments, the cancer or tumor is not hormone-mediated.Non-limiting examples of cancers include, acute lymphoblastic leukemia,acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendixcancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cellcarcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcomaand malignant fibrous histiocytoma), brain stem glioma, brain tumors,brain and spinal cord tumors, breast cancer, bronchial tumors, Burkittlymphoma, cervical cancer, chronic lymphocytic leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, lung cancer, non-small cell lung cancer, smallcell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkinlymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The method of treatment may prevent or reduce the risk of cancer. Themethod of treatment may cause partial or complete regression of cancerin a subject.

The method of treatment may cause partial or complete regression of atamoxifen resistant cancer or tumor. The method of treatment may causepartial or complete regression of a triple negative breast cancer.

In some embodiments, compounds disclosed herein are used to treat orprevent cancer or a tumor in a mammal such as a human. In someembodiments, the cancer is breast cancer, ovarian cancer, endometrialcancer, prostate cancer, or uterine cancer. In some embodiments, thecancer is breast cancer, lung cancer, ovarian cancer, endometrialcancer, prostate cancer, or uterine cancer. In some embodiments, thecancer is breast cancer. In some embodiments, the cancer is a hormonedependent cancer. In some embodiments, the cancer is an estrogenreceptor dependent cancer. In some embodiments, the cancer is anestrogen-sensitive cancer. In some embodiments, the cancer is resistantto anti-hormonal treatment. In some embodiments, the cancer is anestrogen-sensitive cancer or an estrogen receptor dependent cancer thatis resistant to anti-hormonal treatment. In some embodiments, the canceris a hormone-sensitive cancer or a hormone receptor dependent cancerthat is resistant to anti-hormonal treatment. In some embodiments,anti-hormonal treatment includes treatment with at least one agentselected from tamoxifen, fulvestrant, steroidal aromatase inhibitors,and non-steroidal aromatase inhibitors.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, compounds disclosed herein are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal. In some embodiments, the benign ormalignant disease is breast cancer.

In one embodiment a compound of the present invention is used forhormone therapy.

The foregoing may be better understood by reference to the followingExamples, which are presented for purposes of illustration and are notintended to limit the scope of the invention.

In one aspect, a compound of the present invention or itspharmaceutically acceptable salt or prodrug, can be used to treat ahormone-related cancer or tumor that has metastasized to the brain, boneor other organ. In one embodiment of this aspect, the hormone-relatedcancer is estrogen mediated. In another embodiment, the estrogenmediated cancer is selected from breast, uterine, ovarian andendometrial. In other embodiments, a compound of the present inventionor its pharmaceutically acceptable salt or prodrug, can be used toprevent a hormone-related cancer or tumor from metastasizing to thebrain, bone or other organ, including a hormone-related cancer that isestrogen mediated, for example, breast, uterine, ovarian or endometrial.

Combination Therapy

In one aspect, a method for the treatment of a disorder of abnormalcellular proliferation in a host such as a human is provided thatincludes administering an effective amount of a combination of one ormore of the active compounds described herein in combination oralternation with another active compound.

In one aspect of this embodiment, the second active compound is animmune modulator, including but not limited to a checkpoint inhibitor.Checkpoint inhibitors for use in the methods described herein include,but are not limited to PD-1 inhibitors, PD-L1 inhibitors, PD-L2inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, andV-domain Ig suppressor of T-cell activation (VISTA) inhibitors, orcombination thereof.

In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor thatblocks the interaction of PD-1 and PD-L1 by binding to the PD-1receptor, and in turn inhibits immune suppression. In one embodiment,the checkpoint inhibitor is a PD-1 checkpoint inhibitor selected fromnivolumab, pembrolizumab, pidilizumab, AMP-224 (AstraZeneca andMedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001(Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui MedicineCompany and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTAinhibitor CA-170 (Curis Inc.).

In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor thatblocks the interaction of PD-1 and PD-L1 by binding to the PD-L1receptor, and in turn inhibits immune suppression. PD-L1 inhibitorsinclude, but are not limited to, avelumab, atezolizumab, durvalumab,KN035, and BMS-936559 (Bristol-Myers Squibb).

In one aspect of this embodiment, the checkpoint inhibitor is a CTLA-4checkpoint inhibitor that binds to CTLA-4 and inhibits immunesuppression. CTLA-4 inhibitors include, but are not limited to,ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 andAGEN2041 (Agenus).

In another embodiment, the checkpoint inhibitor is a LAG-3 checkpointinhibitor. Examples of LAG-3 checkpoint inhibitors include, but are notlimited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781(GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and thedual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). In yet anotheraspect of this embodiment, the checkpoint inhibitor is a TIM-3checkpoint inhibitor. A specific TIM-3 inhibitor includes, but is notlimited to, TSR-022 (Tesaro).

In yet another embodiment, one of the active compounds described hereinis administered in an effective amount for the treatment of abnormaltissue of the female reproductive system such as breast, ovarian,kidney, endometrial, or uterine cancer, in combination or alternationwith an effective amount of an estrogen inhibitor including but notlimited to a SERM (selective estrogen receptor modulator), a SERD(selective estrogen receptor downregulator), a complete estrogenreceptor downregulator, or another form of partial or complete estrogenantagonist. Partial anti-estrogens like raloxifene and tamoxifen retainsome estrogen-like effects, including an estrogen-like stimulation ofuterine growth, and also, in some cases, an estrogen-like action duringbreast cancer progression which actually stimulates tumor growth. Incontrast, fulvestrant, a complete anti-estrogen, is free ofestrogen-like action on the uterus and is effective intamoxifen-resistant tumors. Non-limiting examples of anti-estrogencompounds are provided in WO 2014/19176 assigned to AstraZeneca.Additional non-limiting examples of anti-estrogen compounds include:SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene,clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene,tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such asaminoglutethimide, testolactone, anastrozole, exemestane, fadrozole,formestane, and letrozole; and antigonadotropins such as leuprorelin,cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate,delmadinone acetate, dydrogesterone, medroxyprogesterone acetate,megestrol acetate, nomegestrol acetate, norethisterone acetate,progesterone, and spironolactone.

In another embodiment, one of the active compounds described herein isadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordownregulator and/or degrader, a complete androgen receptor degrader, oranother form of partial or complete androgen antagonist. In oneembodiment, the prostate or testicular cancer is androgen-resistant.Non-limiting examples of anti-androgen compounds are provided in WO2011/156518 and U.S. Pat. Nos. 8,455,534 and 8,299,112. Additionalnon-limiting examples of anti-androgen compounds include: enzalutamide,apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone,canrenone, drospirenone, ketoconazole, topilutamide, abirateroneacetate, and cimetidine.

In one aspect, a treatment regimen is provided comprising theadministration of a compound of the present invention in combinationwith at least one additional chemotherapeutic agent. The combinationsdisclosed herein can be administered for beneficial, additive, orsynergistic effect in the treatment of abnormal cellular proliferativedisorders.

In specific embodiments, the treatment regimen includes theadministration of a compound of the present invention in combinationwith at least one kinase inhibitor. In one embodiment, the at least onekinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K)inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleentyrosine kinase (Syk) inhibitor, or a combination thereof.

PI3k inhibitors that may be used in the present invention are wellknown. Examples of PI3 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib,GS-9820, GDC-0032(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)—N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide),TGX-221((±)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate),PF-05212384(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N′-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea),LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile),XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)).

In one embodiment, the compound of the present invention is combined ina single dosage form with the PIk3 inhibitor.

BTK inhibitors for use in the present invention are well known. Examplesof BTK inhibitors include ibrutinib (also known asPCI-32765)(Imbruvica™)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see US Patent Publication No 2011/0117073,incorporated herein in its entirety), dasatinib([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide],LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)propenamide), GDC-0834([R—N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide],CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide,CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide),CNX-774(4-(4-((4-(3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide),CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one),GDC-0834((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),GDC-0837((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), QL-47(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one),and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one),and other molecules capable of inhibiting BTK activity, for examplethose BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology& Oncology, 2013, 6:59, the entirety of which is incorporated herein byreference. In one embodiment, the compound of the present invention iscombined in a single dosage form with the BTK inhibitor.

Syk inhibitors for use in the present invention are well known, andinclude, for example, Cerdulatinib(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide),entospletinib(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine),fostamatinib([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyldihydrogen phosphate), fostamatinib disodium salt (sodium(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate), BAY 61-3606(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamideHCl), RO9021(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylicacid amide), imatinib (Gleevec;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide),staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide),PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),PRT-062607(44(3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), R112(3,3′4(5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348(3-Ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one),YM193306(see Singh et al. Discovery and Development of Spleen TyrosineKinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643),7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery andDevelopment of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), Compound D(see Singh et al. Discovery and Development of Spleen Tyrosine Kinase(SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), PRT060318 (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), luteolin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), apigenin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), quercetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), fisetin (see Singh et al. Discovery and Development ofSpleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), myricetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), morin (see Singh et al. Discovery and Development ofSpleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein). In one embodiment, thecompound of the present invention is combined in a single dosage formwith the Syk inhibitor.

In one embodiment, the at least one additional chemotherapeutic agent isa B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors areknown in the art, and include, for example, ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), or G3139 (Oblimersen). In one embodiment, thecompound of the present invention is combined in a single dosage formwith the at least one BCL-2 inhibitor.

The compound of the present invention or its pharmaceutically activesalt can be combined with an immunotherapy. As discussed in more detailbelow, the compound of the present invention can be conjugated to anantibody, radioactive agent, or other targeting agent that directs thecompound to the diseased or abnormally proliferating cell.

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs “coat” the cancer cell surface, triggering its destruction by theimmune system. For example, bevacizumab targets vascular endothelialgrowth factor (VEGF), a protein secreted by tumor cells and other cellsin the tumor's microenvironment that promotes the development of tumorblood vessels. When bound to bevacizumab, VEGF cannot interact with itscellular receptor, preventing the signaling that leads to the growth ofnew blood vessels. Similarly, cetuximab and panitumumab target theepidermal growth factor receptor (EGFR), and trastuzumab targets thehuman epidermal growth factor receptor 2 (HER-2). MAbs, which bind tocell surface growth factor receptors, prevent the targeted receptorsfrom sending their normal growth-promoting signals. They may alsotrigger apoptosis and activate the immune system to destroy tumor cells.

In some embodiments, the combination can be administered to the subjectin further combination with other chemotherapeutic agents. Ifconvenient, the combination described herein can be administered at thesame time as another chemotherapeutic agent in order to simplify thetreatment regimen. In some embodiments, the combination and the otherchemotherapeutic can be provided in a single formulation. In oneembodiment, the use of the compounds described herein is combined in atherapeutic regime with other agents. Such agents may include, but arenot limited to, tamoxifen, midazolam, letrozole, bortezomib,anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitors, dualmTOR-PI3K inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors,HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or acombination thereof), BCL-2 inhibitors, apoptotic compounds, AKTinhibitors, including but not limited to, MK-2206, GSK690693,Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol,PF-04691502, and Miltefosine, PD-1 inhibitors including but not limitedto, Nivolumab, CT-011, MK-3475, BMS936558, and AMP-514 or FLT-3inhibitors, including but not limited to, P406, Dovitinib, Quizartinib(AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, andKW-2449, or combinations thereof. Examples of mTOR inhibitors includebut are not limited to rapamycin and its analogs, everolimus (Afinitor),temsirolimus, ridaforolimus (Deforolimus), and sirolimus. Examples ofMEK inhibitors include but are not limited to trametinib/GSK1120212(N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinib(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC 1935369((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H, 8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330(2-(2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).Examples of RAS inhibitors include but are not limited to Reolysin andsiG12D LODER. Examples of ALK inhibitors include but are not limited toCrizotinib, AP26113, and LDK378. HSP inhibitors include but are notlimited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin(17AAG), and Radicicol. In a particular embodiment, a compound describedherein is administered in combination with letrozole and/or tamoxifen.Other chemotherapeutic agents that can be used in combination with thecompounds described herein include, but are not limited to,chemotherapeutic agents that do not require cell cycle activity fortheir anti-neoplastic effect.

In one embodiment, a compound of the present invention described hereincan be combined with a chemotherapeutic selected from, but are notlimited to, Imatinib mesylate (Gleevec®), Dasatinib (Sprycel®),Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®),Pertuzumab (Perjeta™), Lapatinib (Tykerb®), Gefitinib (Iressa®),Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®),Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®),Romidepsin (Istodax®), Bexarotene (Targretin®), Alitretinoin(Panretin®), Tretinoin (Vesanoid®), Carfilzomib (Kyprolis™),Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept(Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib(Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

In certain aspects, the additional therapeutic agent is ananti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic,additional therapeutic agents, or immunosuppressive agents.

Suitable chemotherapeutic agents include, but are not limited to,radioactive molecules, toxins, also referred to as cytotoxins orcytotoxic agents, which includes any agent that is detrimental to theviability of cells, agents, and liposomes or other vesicles containingchemotherapeutic compounds. General anticancer pharmaceutical agentsinclude: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®),Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®),Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase(Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide(VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™) Examples ofadditional suitable chemotherapeutic agents include but are not limitedto 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, alkylating agents, allopurinolsodium, altretamine, amifostine, anastrozole, anthramycin (AMC)),anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin),diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites,asparaginase, BCG live (intravesical), betamethasone sodium phosphateand betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan,calcium leucovorin, calicheamicin, capecitabine, carboplatin, lomustine(CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine,Colchicine, conjugated estrogens, Cyclophosphamide, Cyclothosphamide,Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine,Dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl,daunorubicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol,dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicinHCl, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, ErwiniaL-asparaginase, esterified estrogens, estradiol, estramustine phosphatesodium, ethidium bromide, ethinyl estradiol, etidronate, etoposidecitrovorum factor, etoposide phosphate, filgrastim, floxuridine,fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinicacid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D,granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferonα-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate,levamisole HCl, lidocaine, lomustine, maytansinoid, mechlorethamine HCl,medroxyprogesterone acetate, megestrol acetate, melphalan HCl,mercaptopurine, Mesna, methotrexate, methyltestosterone, mithramycin,mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate,ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin,pilocarpine HCl, plicamycin, polifeprosan 20 with carmustine implant,porfimer sodium, procaine, procarbazine HCl, propranolol, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, teniposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCl,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith a compound disclosed herein can include 2-methoxyestradiol or 2ME2,finasunate, vatalanib, volociximab, etaracizumab (MEDI-522),cilengitide, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab,aldesleukin, atlizumab, tocilizumab, lucatumumab, dacetuzumab, HLL1,huN901-DM1, atiprimod, natalizumab, bortezomib, marizomib, tanespimycin,saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate,belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin,plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, lenalidomide,thalidomide, pomalidomide, simvastatin, and celecoxib.

In one aspect of the present invention, a compound described herein canbe combined with at least one immunosuppressive agent. Theimmunosuppressive agent in one embodiment is selected from the groupconsisting of a calcineurin inhibitor, e.g. a cyclosporin or anascomycin, e.g. Cyclosporin A (Neoral®), FK506 (tacrolimus),pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof,e.g. Sirolimus (Rapamune®), Everolimus (Certican®), temsirolimus,zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus,azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod oran analogue thereof, an anti-IL-8 antibody, mycophenolic acid or a saltthereof, e.g. sodium salt, or a prodrug thereof, e.g. MycophenolateMofetil (CellCept®), OKT3 (Orthoclone OKT3®), Prednisone, ATGAM®,Thymoglobulin®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide Arava®, anti-CD25,anti-IL2R, Basiliximab (Simulect®), Daclizumab (Zenapax®), mizoribine,methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus,Elidel®), CTLA4lg, Abatacept, belatacept, LFA3lg, etanercept (sold asEnbrel® by ImmuneXcite), adalimumab (Humira®), infliximab (Remicade®),an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab,Golimumab, antithymocyte immunoglobulin, siplizumab, Alefacept,efalizumab, Pentasa, mesalazine, asacol, codeine phosphate, benorylate,fenbufen, naprosyn, diclofenac, etodolac, indomethacin, aspirin, andibuprofen.

In certain embodiments, a compound described herein is administered tothe subject prior to treatment with another chemotherapeutic agent,during treatment with another chemotherapeutic agent, afteradministration of another chemotherapeutic agent, or a combinationthereof.

Synthetic Methods

The compounds described herein can be prepared by methods known by thoseskilled in the art. In one non-limiting example the disclosed compoundscan be prepared using the schemes. As used herein alkenylene canencompass both cis and trans isomers of alkenes, unless indicatedotherwise. In one embodiment the isomer is cis. In a preferredembodiment the isomer is trans. In one embodiment R₂ is—C₂-C₆alkenylene-COOR₁₇ and the alkene group is cis. In a preferredembodiment R₂ is —C₂-C₆alkenylene-COOR₁₇ and the alkene group is trans.

Some of the compounds described herein can have a chiral center, and thecompound can exist in isomeric or diastereomeric form. When multiplechiral variables are present on formulas of the present invention, theformula further encompasses every possible diastereomer unless indicatedotherwise. For example (R,R), (S,R), (S,S), and (R,S) for a moleculewith two chiral centers. One skilled in the art will recognize that pureenantiomers, diastereomers, and cis/trans isomers can be prepared bymethods known in the art. Examples of methods to obtain optically activematerials include at least the following:

i) Physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) Simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) Enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme;

iv) Enzymatic asymmetric synthesis—a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) Chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor underconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

vi) Diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) First- and second-order asymmetric transformations—a techniquewhereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) Kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst underkinetic conditions;

ix) Enantiospecific synthesis from non-racemic precursors—a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) Chiral liquid chromatography—a technique whereby the enantiomers of aracemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase (including via chiralHPLC). The stationary phase can be made of chiral material or the mobilephase can contain an additional chiral material to provoke the differinginteractions;

xi) Chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) Extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent;

xiii) Transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane that allowsonly one enantiomer of the racemate to pass through.

xiv) Simulated moving bed chromatography, is used in one embodiment. Awide variety of chiral stationary phases are commercially available.

General Synthetic Route 1:

General Synthetic Route 2:

General Synthetic Route 3:

General Synthetic Route 4:

General Synthetic Route 5:

Intermediate 1:3-Chloro-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide

In an oven-dried round-bottom flask,3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (8.9 g, 34.9mmol) was dissolved in 50 mL of anhydrous dichloromethane under argonatmosphere and N,O-dimethylhydroxylamine hydrochloride (3.75 g, 38.4mmol) was added in one portion. After stirring for 10 minutes, Et₃N(17.6 g, 174.5 mmol) was added dropwise. The reaction mixture wasstirred overnight until TLC indicated consumption of all startingmaterials. The reaction was quenched by ice water, the solution wasextracted with ethyl acetate, and washed with brine. The organicextracts were combined, dried over anhydrous Na₂SO₄, concentrated invacuum, and purified by flash chromatography (5%-50% ethyl acetate inhexane) to afford 7.6 g as a white solid (76%). ¹H NMR (400 MHz, CDCl₃)δ 7.82 (d, J=8.9 Hz, 1H), 7.23 (s, 1H), 7.10 (dd, J=8.9, 2.3 Hz, 1H),3.90 (s, 3H), 3.73 (s, 3H), 3.39 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ162.04, 159.88, 140.35, 130.23, 124.19, 116.09, 104.29, 62.04, 55.87,33.75.

Intermediate 2:(3-Chloro-6-methoxybenzo[b]thiophen-2-yl)(4-fluoro-2-methylphenyl)methanone

To a solution of intermediate (1) (500 mg, 1.75 mmol) in THF under argonatmosphere was added a 0.5 M solution of(4-fluoro-2-methylphenyl)magnesium bromide (4 mL, 2 mmol) dropwise. Thereaction mixture was stirred overnight and quenched by 1 N HCl/icewater. The solution was extracted with ethyl acetate and washed withbrine. The organic extracts were combined, dried over anhydrous Na₂SO₄,concentrated in vacuum, and purified by flash chromatography (1%-15%ethyl acetate in hexane) to afford 550 mg of a white solid (94%).

The following intermediates were made by an analogous procedureutilizing the appropriate Grignard reagent:

(3-Chloro-6- methoxybenzo[b]thiophen- 2-yl)(4- methoxyphenyl)methanone¹H NMR (400 MHz, CDCl₃) δ 7.93-7.86 (m, 2H), 7.81 (d, J = 8.9 Hz, 1H),7.25 (d, J = 1.5 Hz, 1H), 7.11 (dd, J = 8.9, 2.2 Hz, 1H), 7.00-6.88 (m,2H), 3.90 (s, 3H), 3.89 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 187.57,163.95, 160.22, 140.70, 132.50, 132.12, 131.07, 130.63, 124.64, 123.70,116.54, 113.83, 104.54, 55.91, 55.67.

(3-Chloro-6- methoxybenzo[b]thiophen- 2-yl)(2- ethylphenyl)methanone ¹HNMR (400 MHz, CDCl₃) δ 7.80 (d, J = 9.0 Hz, 1H), 7.45 (td, J = 7.6, 1.3Hz, 1H), 7.40-7.32 (m, 2H), 7.30-7.26 (m, 1H), 7.24 (d, J = 2.2 Hz, 1H),7.09 (dd, J = 9.0, 2.3 Hz, 1H), 3.91 (s, 3H), 2.74 (q, J = 7.5 Hz, 2H),1.21 (t, J = 7.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 191.07, 160.96,142.52, 141.85, 139.10, 134.02, 131.67, 130.80, 129.48, 127.86, 125.73,125.36, 116.86, 104.50, 55.92, 26.38, 15.81.

(3-Chloro-6- methoxybenzo[b]thiophen- 2-yl)(phenyl)methanone ¹H NMR (400MHz, CDCl₃) δ 7.92-7.78 (m, 3H), 7.61 (t, J = 7.4 Hz, 1H), 7.49 (t, J =7.6 Hz, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.12 (dd, J = 9.0, 2.3 Hz, 1H),3.92 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 188.94, 160.37, 140.96, 138.08,132.88, 131.76, 131.05, 129.56, 128.34, 124.86, 124.77, 116.59, 104.31,55.76.

(3-Chloro-6- methoxybenzo[b]thiophen- 2-yl)(o-tolyl)methanone ¹H NMR(400 MHz, CDCl₃) δ 7.80 (d, J = 9.0 Hz, 1H), 7.45- 7.35 (m, 2H),7.34-7.19 (m, 3H), 7.09 (dd, J = 9.0, 2.3 Hz, 1H), 3.91 (s, 3H), 2.39(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 191.06, 160.90, 141.81, 139.41,136.21, 133.86, 131.59, 131.03, 130.72, 127.93, 126.44, 125.77, 125.32,116.86, 104.45, 55.91, 19.70.

(3-chloro-6- methoxybenzo[b]thiophen- 2-yl)(5-fluoro-2-methylphenyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J = 9.0 Hz,1H), 7.26-7.23 (m, 2H), 7.13-7.08 (m, 3H), 3.92 (s, 3H), 2.32 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 189.59, 161.17, 160.92 (d, J = 245.5 Hz),142.07, 140.77 (d, J = 6.3 Hz), 133.30, 132.55 (d, J = 7.4 Hz), 131.64(d, J = 3.5 Hz), 131.58, 127.03, 125.48, 117.45 (d, J = 21.0 Hz),117.06, 114.61 (d, J = 23.0 Hz), 104.52, 55.95, 18.84.

(3-chloro-6- methoxybenzo[b]thiophen- 2-yl)(3-methylthiophen-2-yl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.9 Hz, 1H), 7.54(d, J = 4.9 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 8.9, 2.2Hz, 1H), 6.99 (d, J = 4.9 Hz, 1H), 3.91 (s, 3H), 2.50 (s, 3H). ¹³C NMR(100 MHz, CDCl₃) δ 181.18, 160.26, 146.19, 140.41, 135.96, 132.23,132.15, 131.81, 130.83, 124.63, 124.02, 116.64, 104.52, 55.89, 16.40.

(3-chloro-6- methoxybenzo[b]thiophen- 2-yl)(2,4-dimethylphenyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 9.0 Hz,1H), 7.33 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.10-7.00 (m,3H), 3.87 (s, 3H), 2.37 (s, 6H).

Intermediate 3:(3-Chloro-6-methoxybenzo[b]thiophen-2-yl)(2-(trifluoromethyl)phenyl)methanone

To a solution of 3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride(1.04 g, 4 mmol) in THF under argon atmosphere was added a freshlyprepared solution of (2-(trifluoromethyl)phenyl)magnesium bromide (5mmol) dropwise. The reaction mixture was stirred overnight and quenchedby 1 N HCl/ice water. The solution was extracted with ethyl acetate andwashed with brine. The organic extracts were combined, dried overanhydrous Na₂SO₄, concentrated in vacuum, and purified by flashchromatography (1%-15% ethyl acetate in hexane) to afford 350 mg of awhite solid (19%). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (t, J=8.3 Hz, 2H),7.70-7.57 (m, 2H), 7.47 (d, J=6.4 Hz, 1H), 7.24 (s, 1H), 7.07 (dd,J=9.0, 1.9 Hz, 1H), 3.90 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 187.86,161.27, 142.29, 138.58 (q, J=2.1 Hz), 133.23, 131.99, 131.49, 130.20,127.88, 127.75, 127.69 (q, J=32.3 Hz), 126.89 (q, J=4.5 Hz), 125.49,123.70 (q, J=274.0 Hz), 117.07, 104.41, 55.91. ¹⁹F NMR (400 MHz, CDCl₃)δ −58.46.

The following intermediates were made by an analogous procedureutilizing the appropriate Grignard reagent:

(2-Chloro-4- fluorophenyl)(3-chloro-6- methoxybenzo[b]thiophen-2-yl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 9.0 Hz, 1H), 7.43(dd, J = 8.5, 5.9 Hz, 1H), 7.24-7.16 (m, 2H), 7.13-7.02 (m, 2H), 3.90(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 186.58, 163.57 (d, J = 253.9 Hz),161.19, 142.19, 135.45 (d, J = 3.7 Hz), 133.24, 132.81 (d, J = 10.6 Hz),131.39, 130.35 (d, J = 9.4 Hz), 127.28, 125.42, 117.63 (d, J = 24.9 Hz),117.03, 114.63 (d, J = 21.6 Hz), 104.40, 55.87.

(3-Chloro-6- methoxybenzo[b]thiophen- 2-yl)(2,6-dimethylphenyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 9.0 Hz,1H), 7.26-7.18 (m, 2H), 7.12-7.02 (m, 3H), 3.90 (s, 3H), 2.22 (s, 6H).¹³C NMR (100 MHz, CDCl₃) δ 192.58, 161.14, 142.18, 140.22, 134.18,131.75, 129.31, 127.84, 126.81, 125.55, 116.91, 104.53, 55.91, 19.31.

Compound I-4:(3-(4-Bromophenoxy)-6-methoxybenzo[b]thiophen-2-yl)(4-fluoro-2-methylphenyl)methanone

Cs₂CO₃ (1.52 g, 4.67 mmol) was added in one portion to a solution ofintermediate 2 (520 mg, 1.56 mmol) and 4-bromophenol in 5 mL DMF. Thereaction mixture was raised to 50° C. and after stirring overnight, thereaction mixture was quenched with ice water, extracted with ethylacetate, and washed with brine. The organic extracts were combined,dried over anhydrous Na₂SO₄, concentrated in vacuum, and purified byflash chromatography (1%-15% ethyl acetate in hexane) to afford 490 mgwhite solid (67%). ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=8.9 Hz, 1H),7.34-7.27 (m, 2H), 7.22-7.17 (m, 2H), 6.96 (dd, J=8.9, 2.2 Hz, 1H),6.80-6.76 (m, 2H), 6.40-6.33 (m, 2H), 3.91 (s, 3H), 2.16 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 189.34, 163.72 (d, J=250.2 Hz), 161.07, 157.45,148.25, 142.21, 139.63 (d, J=8.6 Hz), 135.29 (d, J=3.1 Hz), 132.38,130.24 (d, J=9.2 Hz), 126.82, 127.48, 124.57, 117.45 (d, J=21.4 Hz),116.74, 116.55, 115.09, 112.19 (d, J=21.7 Hz), 105.19, 55.89, 19.53 (d,J=1.3 Hz).

The following Compounds were made by an analogous procedure utilizingthe appropriate starting materials:

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(4- methoxyphenyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.9 Hz, 2H), 7.47 (d, J= 8.9 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.98(dd, J = 8.9, 2.2 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.54 (d, J = 9.0Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ ¹³C NMR(100 MHz, CDCl₃) δ 187.33, 163.49, 160.43, 157.45, 146.58, 141.29,132.47, 131.84, 130.92, 126.71, 125.99, 124.18, 117.46, 116.23, 115.05,113.43, 105.08, 55.87, 55.64.

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(2- ethylphenyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J = 8.9 Hz, 1H), 7.29-7.24(m, 3H), 7.17-7.13 (m, 3H), 7.07 (t, J = 7.5 Hz, 1H), 6.94 (dd, J = 8.9,2.2 Hz, 1H), 6.35- 6.29 (m, 2H), 3.91 (s, 3H), 2.50 (q, J = 7.5 Hz, 2H),1.06 (t, J = 7.6 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 190.68, 160.98,157.30, 148.30, 142.19, 142.15, 138.95, 132.27, 130.35, 128.91, 128.06,127.55, 126.90, 125.21, 124.66, 116.93, 116.46, 114.91, 105.22, 55.89,26.21, 15.62.

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2- yl)(phenyl)methanone¹H NMR (400 MHz, CDCl₃) δ 7.72- 7.65 (m, 2H), 7.52-7.44 (m, 2H), 7.34(t, J = 7.7 Hz, 2H), 7.28 (d, J = 2.1 Hz, 1H), 7.21-7.15 (m, 2H), 6.97(dd, J = 8.9, 2.2 Hz, 1H), 6.49-6.43 (m, 2H), 3.92 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 188.95, 160.72, 157.40, 147.59, 141.76, 138.49, 132.47,132.40, 129.02, 128.09, 126.72, 125.92, 124.44, 117.33, 116.40, 115.07,105.10, 55.88.

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(o-tolyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 8.9 Hz, 1H),7.29-7.20 (m, 3H), 7.18- 7.12 (m, 2H), 7.11-7.04 (m, 2H), 6.95 (dd, J =8.9, 2.2 Hz, 1H), 6.37- 6.26 (m, 2H), 3.91 (s, 3H), 2.16 (s, 3H). ¹³CNMR (100 MHz, CDCl₃) δ 190.66, 160.99, 157.45, 148.38, 142.20, 139.30,135.92, 132.27, 130.63, 130.28, 127.74, 127.63, 126.92, 125.25, 124.60,116.86, 116.48, 114.92, 105.20, 55.89, 19.36.

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(5- fluoro-2-methylphenyl) methanone ¹H NMR (400 MHz, CDCl₃) δ 7.41 (d, J = 8.9 Hz,1H), 7.28 (d, J = 2.1 Hz, 1H), 7.19 (d, J = 9.0 Hz, 2H), 7.04-6.91 (m,4H), 6.38 (d, J = 9.0 Hz, 2H), 3.91 (s, 3H), 2.11 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 189.11, 161.19, 160.60 (d, J = 245.3 Hz), 157.28, 148.76,142.47, 140.60 (d, J = 6.3 Hz), 132.42, 132.06 (d, J = 7.4 Hz), 131.36(d, J = 3.5 Hz), 127.15, 126.70, 124.75, 116.90 (d, J = 20.9 Hz),116.76, 116.64, 115.15, 114.34 (d, J = 23.0 Hz), 105.22, 55.90, 18.56.

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(3-methylthiophen-2- yl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J =8.9 Hz, 1H), 7.42 (d, J = 4.9 Hz, 1H), 7.28-7.23 (m, 3H), 6.99 (dd, J =8.9, 2.2 Hz, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.67- 6.59 (m, 2H), 3.91 (s,3H), 2.34 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 181.10, 160.50, 157.62,147.31, 145.02, 140.99, 135.76, 132.50, 131.63, 130.84, 126.58, 125.44,124.19, 117.62, 116.31, 115.25, 104.96, 55.87, 15.94.

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(2-(trifluoromethyl) phenyl)methanone ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J= 7.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H),7.33-7.28 (m, 1H), 7.27-7.21 (m, 2H), 7.18 (d, J = 8.9 Hz, 2H), 6.89(dd, J = 8.9, 2.2 Hz, 1H), 6.33 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H).

(3-(4- Bromophenoxy)-6- methoxybenzo[b] thiophen-2-yl)(2,6-dimethylphenyl) methanone ¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 8.9 Hz,1H), 7.28 (d, J = 2.1 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 7.04 (t, J =7.6 Hz, 1H), 6.92 (dd, J = 8.9, 2.2 Hz, 1H), 6.86 (d, J = 7.7 Hz, 2H),6.34 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H), 2.11 (s, 6H). ¹³C NMR (100 MHz,CDCl₃) δ 192.08, 160.94, 156.72, 148.28, 142.22, 140.16, 133.71, 131.95,128.73, 128.49, 127.35, 126.59, 124.67, 116.52, 116.40, 114.74, 105.22,55.75, 19.18.

Methyl 7-((6- methoxy-2-(2- methylbenzoyl)benzo [b]thiophen-3-yl)oxy)quinoline-3- carboxylate ¹H NMR (400 MHz, CDCl₃) δ 9.29 (d, J =1.7 Hz, 1H), 8.71 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.45 J = 8.9 Hz,1H), 7.30 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.16 (t, J =7.3 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 6.99-6.88 (m, 3H), 6.83 (dd, J =8.9, 2.3 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 2.04 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 190.40, 165.93, 161.07, 160.98, 150.88, 150.81, 147.66,142.34, 139.30, 138.37, 135.65, 130.48, 130.41, 130.14, 128.07, 127.33,126.64, 125.14, 124.40, 122.83, 121.83, 118.87, 116.73, 111.31, 105.15,55.89, 52.53, 19.22.

Methyl 6-((6- methoxy-2-(2- methylbenzoyl)benzo [b]thiophen-3-yl)oxy)-2- naphthoate ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 1H), 7.96 (dd,J = 8.6, 1.5 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 8.7 Hz,1H), 7.47 (d, J = 8.9 Hz, 1H), 7.32- 7.27 (m, 2H), 7.16 (t, J = 7.5 Hz,1H), 6.98 (t, J = 7.5 Hz, 1H), 6.95-6.86 (m, 2H), 6.77 (d, J = 2.2 Hz,1H), 6.73 (dd, J = 8.9, 2.5 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 1.99(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 190.43, 167.05, 160.88, 158.00,148.20, 142.08, 139.06, 136.21, 135.72, 131.02, 130.70, 130.36, 130.05,128.52, 127.67, 127.47, 127.05, 126.85, 126.09, 126.02, 125.04, 124.43,117.70, 116.38, 109.49, 105.09, 55.69, 52.11, 19.06.

Methyl (E)-3-(4-((2- (2,4- dimethylbenzoyl)-6- methoxybenzo[b]thiophen-3- yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J= 16.0 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.23(t, J = 8.9 Hz, 3H), 6.96 (dd, J = 8.9, 2.2 Hz, 1H), 6.85 (d, J = 11.2Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 16.0 Hz, 1H), 3.91 (s,3H), 3.79 (s, 3H), 2.29 (s, 3H), 2.09 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)δ 190.48, 167.65, 160.87, 160.01, 147.81, 144.09, 141.92, 140.64,136.30, 136.22, 131.40, 129.33, 128.91, 128.29, 127.79, 127.05, 125.79,124.43, 116.48, 116.43, 115.58, 105.11, 55.87, 51.79, 21.47, 19.38.

Methyl (E)-3-(4-((2- (2-chloro-4- fluorobenzoyl)-6- methoxybenzo[b]thiophen-3- yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J= 16.0 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.28 (t, J = 8.8 Hz, 3H), 7.20(dd, J = 8.5, 5.9 Hz, 1H), 7.00 (dd, J = 8.6, 2.3 Hz, 1H), 6.93 (dd, J =9.0, 2.2 Hz, 1H), 6.81 (td, J = 8.3, 2.4 Hz, 1H), 6.55 (d, J = 8.7 Hz,2H), 6.29 (d, J = 16.0 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 186.10, 167.53, 163.16 (d, J = 253.1 Hz), 161.27, 159.30,148.85, 143.81, 142.73, 135.48 (d, J = 3.7 Hz), 132.49 (d, J = 10.6 Hz),129.79 (d, J = 9.3 Hz), 129.56, 129.36, 127.18, 126.36, 124.83, 117.18(d, J = 24.9 Hz), 116.91, 116.72, 115.45, 113.83 (d, J = 21.6 Hz),105.22, 55.91, 51.82.

Compound I-5:(3-(4-Bromophenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2-methylphenyl)methanone

Compound I-4 (480 mg, 1 mmol) was dissolved in 10 mL of anhydrousdichloromethane at room temperature and BF₃.SMe₂ (1.2 ml, 5 mmol) wasadded dropwise to this solution. The reaction mixture was stirred untilstarting material, as monitored by TLC, was consumed. The reaction wasthen quenched with saturated NaHCO₃/ice water, extracted with ethylacetate, and washed with brine. The organic extracts were combined,dried over anhydrous Na₂SO₄, concentrated in vacuum, and purified byflash chromatography (5%-60% ethyl acetate in hexane) to afford 390 mgas a white powder (85%). ¹H NMR (400 MHz, MeOD) δ 7.38 (d, J=8.8 Hz,1H), 7.35-7.28 (m, 1H), 7.28-7.20 (m, 3H), 6.90 (dd, J=8.8, 2.1 Hz, 1H),6.87-6.80 (m, 2H), 6.46-6.38 (m, 2H), 2.13 (s, 3H).

The following compounds were made by an analogous procedure utilizingappropriate starting materials:

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl) (4-hydroxyphenyl) methanone ¹H NMR (400 MHz, Acetone) δ 7.71 (d, J = 8.7Hz, 2H), 7.47 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.35 (d, J= 9.0 Hz, 2H), 7.02 (dd, J = 8.8, 2.1 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H),6.68 (d, J = 9.0 Hz, 2H).

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl) (2- ethylphenyl)methanone ¹H NMR (400 MHz, Acetone) δ 9.25 (s, 1H), 7.44-7.38 (m, 2H),7.35-7.26 (m, 4H), 7.19 (d, J = 7.5 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H),6.99 (dd, J = 8.8, 2.2 Hz, 1H), 6.52-6.44 (m, 2H), 2.49 (q, J = 7.5 Hz,2H), 1.04 (t, J = 7.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 190.58,159.88, 158.26, 149.03, 142.77, 142.50, 140.15, 133.10, 130.97, 129.63,128.13, 128.05, 126.79, 126.01, 125.59, 118.04, 117.20, 115.18, 108.98,26.72, 15.95.

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2- yl)(phenyl)methanone ¹H NMR (400 MHz, MeOD) δ 7.62 (d, J = 7.2 Hz, 2H), 7.51 (t, J= 7.5 Hz, 1H), 7.44-7.32 (m, 3H), 7.25-7.21 (m, 3H), 6.91 (dd, J = 8.8,2.1 Hz, 1H), 6.49 (d, J = 9.0 Hz, 2H). ¹³C NMR (101 MHz, MeOD) δ 190.76,160.50, 158.77, 149.54, 143.24, 139.95, 133.47, 133.38, 129.69, 129.14,126.80, 125.81, 125.53, 118.42, 117.39, 115.88, 108.74.

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl) (o-tolyl)methanone ¹H NMR (400 MHz, MeOD) δ 7.36 (d, J = 8.8 Hz, 1H),7.30-7.17 (m, 5H), 7.09 (t, J = 7.4 Hz, 2H), 6.89 (dd, J = 8.8, 2.1 Hz,1H), 6.41-6.32 (m, 2H), 2.11 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ 192.45,160.86, 158.79, 150.45, 143.73, 140.77, 136.58, 133.33, 131.53, 131.27,128.38, 127.60, 126.95, 126.34, 125.74, 117.99, 117.49, 115.77, 108.88,19.29.

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl) (5- fluoro-2-methylphenyl) methanone ¹H NMR (400 MHz, Acetone) δ 7.44- 7.41 (m, 2H),7.33 (d, J = 9.0 Hz, 2H), 7.18-7.13 (m, 1H), 7.09 (dd, J = 8.9, 2.7 Hz,1H), 7.05-6.99 (m, 2H), 6.54 (d, J = 9.0 Hz, 2H), 2.11 (s, 3H). ¹³C NMR(101 MHz, CDCl₃) δ 189.08, 161.39 (d, J = 243.4 Hz), 160.11, 158.23,149.48, 143.09, 142.07 (d, J = 6.4 Hz), 133.24, 132.96 (d, J = 7.6 Hz),131.83 (d, J = 3.4 Hz), 127.43, 126.60, 125.72, 117.91, 117.34, 117.29(d, J = 21.3 Hz), 115.39, 114.60 (d, J = 23.2 Hz), 109.04, 18.45.

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl)(3-methylthiophen- 2-yl) methanone ¹H NMR (400 MHz, Acetone-d6) δ 9.19(s, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.42 (d, J= 2.1 Hz, 1H), 7.39-7.32 (m, 2H), 7.04 (dd, J = 8.8, 2.1 Hz, 1H), 6.97(d, J = 4.9 Hz, 1H), 6.74-6.65 (m, 2H), 2.29 (s, 3H). ¹³C NMR (100 MHz,Acetone-d6) δ 181.07, 159.40, 158.68, 147.89, 144.79, 141.57, 136.57,133.26, 132.38, 131.63, 126.53, 125.63, 124.95, 118.55, 117.13, 115.47,108.74, 15.70.

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl) (2-(trifluoromethyl) phenyl) methanone ¹H NMR (400 MHz, MeOD) δ 7.58 (d, J= 7.8 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.31(d, J = 7.2 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.19-7.09 (m, 3H), 6.80(dd, J = 8.9, 2.1 Hz, 1H), 6.31 (d, J = 9.0 Hz, 2H).

(3-(4- Bromophenoxy)-6- hydroxybenzo[b] thiophen-2-yl)(2,6-dimethylphenyl) methanone ¹H NMR (400 MHz, Acetone) δ 9.29 (s, 1H), 7.43(d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 9.0 Hz, 2H),7.06 (t, J = 7.6 Hz, 1H), 6.98 (dd, J = 8.8, 2.1 Hz, 1H), 6.90 (d, J =7.5 Hz, 2H), 6.46 (d, J = 8.9 Hz, 2H), 2.08 (s, 6H). ¹³C NMR (100 MHz,Acetone) δ 191.96, 159.98, 157.87, 149.06, 142.90, 141.45, 134.37,132.90, 129.46, 128.64, 128.13, 126.65, 125.75, 117.72, 117.26, 115.12,109.12, 19.29.

Compound I-6: Methyl(E)-3-(4-((2-(4-fluoro-2-methylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate

In a sealed tube, compound 1-5 (200 mg, 0.46 mmol), methyl acrylate (240mg, 2.76 mmol), and Pd(PPh₃)₂Cl₂ were suspended in DMF (2 ml) andtriethylamine (235 mg, 2.3 mmol). The reaction was heated at 110° C. for6 hours. The reaction mixture was quenched by water and extracted withethyl acetate. The organic layers was collected and purified by flashchromatography (5%-60% ethyl acetate in hexane) to afford 170 mg as awhite powder (85%). ¹H NMR (400 MHz, MeOD) δ 7.57 (d, J=16.0 Hz, 1H),7.40-7.36 (m, 3H), 7.32 (dd, J=8.8, 6.0 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H),6.89 (m J=8.9, 1.9 Hz, 1H), 6.83-6.78 (m, 2H), 6.52 (d, J=8.7 Hz, 2H),6.37 (d, J=16.0 Hz, 1H), 3.76 (s, 3H), 2.10 (s, 3H). ¹³C NMR (100 MHz,MeOD) δ 191.09, 169.17, 164.95 (d, J=248.7 Hz), 161.19, 160.91, 150.13,145.22, 143.71, 140.41 (d, J=8.6 Hz), 136.86 (d, J=3.0 Hz), 131.11 (d,J=9.2 Hz), 130.77, 130.47, 127.59, 126.92, 125.70, 118.13 (d, J=21.8Hz), 117.55, 117.48, 116.47, 113.11 (d, J=21.9 Hz), 108.89, 52.09,19.41.

The following compounds were made by an analogous procedure utilizingappropriate starting materials:

Methyl (E)-3-(4-((6- hydroxy-2-(4- hydroxybenzoyl) benzo[b]thiophen-3-yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.7 Hz,2H), 7.55 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.39 (d, J =8.8 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.8, 2.1 Hz, 1H),6.74 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 6.35 (d, J = 16.0Hz, 1H), 3.74 (s, 3H)

Methyl (E)-3-(4-((2- (2-ethylbenzoyl)-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.57 (d, J = 16.0 Hz,1H), 7.40-7.20 (m, 6H), 7.14 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.5 Hz,1H), 6.88 (dd, J = 8.8, 2.1 Hz, 1H), 6.47 (d, J = 8.8 Hz, 2H), 6.36 (d,J = 16.0 Hz, 1H), 3.76 (s, 3H), 2.46 (q, J = 7.5 Hz, 2H), 1.02 (t, J =7.6 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 192.46, 169.17, 161.00, 160.81,150.20, 145.31, 143.66, 142.87, 140.35, 131.30, 130.70, 130.29, 129.89,128.29, 127.97, 126.89, 126.30, 125.79, 117.47, 117.31, 116.67, 108.90,52.09, 27.10, 15.96.

Methyl (E)-3-(4-((2- benzoyl-6- hydroxybenzo[b] thiophen-3-yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 7.65 (d,J = 7.9 Hz, 2H), 7.56- 7.52 (m, 4H), 7.39-7.34 (m, 4H), 6.93 (d, J = 8.8Hz, 1H), 6.66 (d, J = 8.5 Hz, 2H), 6.47 (d, J = 16.1 Hz, 1H), 3.69 (s,3H). ¹³C NMR (101 MHz, DMSO) δ 187.95, 166.69, 159.08, 158.90, 147.19,143.62, 141.00, 138.11, 132.27, 130.10, 128.67, 128.32, 128.03, 124.63,124.32, 124.29, 116.55, 116.51, 115.66, 108.03, 51.37.

Methyl (E)-3-(4-((6- hydroxy-2-(2- methylbenzoyl) benzo[b]thiophen-3-yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.56 (d, J = 16.0 Hz,1H), 7.35 (d, J = 8.6 Hz, 3H), 7.28-7.21 (m, 3H), 7.10-7.01 (m, 2H),6.88 (dd, J = 8.8, 2.1 Hz, 1H), 6.46 (d, J = 8.7 Hz, 2H), 6.35 (d, J =16.0 Hz, 1H), 3.76 (s, 3H), 2.09 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ192.43, 169.18, 161.17, 160.84, 150.28, 145.31, 143.69, 140.72, 136.56,131.51, 131.25, 130.70, 130.31, 128.36, 127.69, 126.95, 126.32, 125.73,117.49, 117.33, 116.58, 108.90, 52.09, 19.31.

Methyl (E)-3-(4-((2- (5-fluoro-2- methylbenzoyl)-6- hydroxybenzo[b]thiophen-3- yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.55 (d, J= 16.0 Hz, 1H), 7.38-7.31 (m, 3H), 7.26 (d, J = 2.1 Hz, 1H), 7.09-7.00(m, 1H), 6.99-6.92 (m, 2H), 6.87 (dd, J = 8.9, 2.1 Hz, 1H), 6.50 (d, J =8.7 Hz, 2H), 6.35 (d, J = 16.0 Hz, 1H), 3.75 (s, 3H), 2.06 (s, 3H). ¹³CNMR (100 MHz, MeOD) δ 190.64, 169.15, 161.89 (d, J = 244.5 Hz), 161.01,160.96, 150.54, 145.21, 143.94, 142.19 (d, J = 6.4 Hz), 133.17 (d, J =7.5 Hz), 132.14 (d, J = 3.4 Hz), 130.80, 130.47, 127.31, 126.75, 125.87,117.62 (d, J = 21.3 Hz), 117.60, 117.45, 116.49, 114.83 (d, J = 23.3Hz), 108.94, 52.09, 18.49.

Methyl (E)-3-(4-((6- hydroxy-2-(3- methylthiophene-2- carbonyl)benzo[b]thiophen-3- yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.61- 7.55(m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.28 (d, J= 2.1 Hz, 1H), 6.98-6.87 (m, 2H), 6.71 (d, J = 8.7 Hz, 2H), 6.38 (d, J =16.0 Hz, 1H), 3.77 (s, 3H), 2.24 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ182.78, 169.15, 161.50, 160.27, 148.90, 145.52, 145.28, 142.40, 136.89,132.55, 132.19, 130.85, 130.50, 126.82, 125.53, 125.13, 117.39, 117.09,108.64, 52.09, 15.67.

Methyl (E)-3-(4-((6- hydroxy-2-(2- (trifluoromethyl) benzoyl)benzo[b]thiophen-3- yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.58 (d, J= 7.8 Hz, 1H), 7.52 (d, J = 16.0 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H),7.38- 7.21 (m, 5H), 7.17 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.0 Hz,1H), 6.42 (d, J = 8.7 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H), 3.71 (s, 3H).¹³C NMR (100 MHz, MeOD) δ 188.88, 169.00, 160.87, 160.11, 150.85,145.06, 143.97, 139.62 (q,J = 1.9 Hz), 132.62, 130.84, 130.65, 130.39,128.51, 127.81 (q, J = 32.0 Hz), 127.29, 127.26 (q, J = 4.5 Hz), 126.13,126.02, 125.02 (q, J = 273.4 Hz), 117.48, 117.42, 116.64, 109.01, 52.10.¹⁹F NMR (400 MHz, MeOD) δ −57.84.

Methyl (E)-3-(4-((2- (2,6- dimethylbenzoyl)-6- hydroxybenzo[b]thiophen-3- yl)oxy)phenyl) acrylate ¹H NMR (400 MHz, MeOD) δ 7.57 (d, J= 16.0 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.30-7.24 (m, 2H), 7.03 (t, J= 7.6 Hz, 1H), 6.88-6.80 (m, 3H), 6.45 (d, J = 8.7 Hz, 2H), 6.36 (d, J =16.0 Hz, 1H), 3.75 (s, 3H), 2.06 (s, 6H). ¹³C NMR (100 MHz, MeOD) δ194.05, 169.17, 160.99, 160.62, 150.45, 145.33, 143.89, 141.52, 134.80,130.57, 130.30, 129.92, 128.47, 126.75, 125.99, 117.57, 117.27, 116.42,109.04, 52.10, 19.34.

Example 1: Synthetic Procedures for Representative Compounds(E)-3-(4-((2-(4-Fluoro-2-methylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylicacid (Compound 1)

To a solution of Compound I-6 (75 mg, 0.16 mmol) in methanol (2 ml) wasadded 10% LiOH solution (2 ml) dropwise. The reaction was monitored byTLC and once TLC indicated consumption of starting materials, thereaction was quenched by 1 N HCl/ice water. After stirring for 10minutes, the mixture was extracted with ethyl acetate. The organiclayers were collected and purified by C18 chromatography (5%-60% ethylmethanol in water) to afford 71 mg as a white powder (99%). ¹H NMR (400MHz, CDCl₃) δ 7.58 (d, J=16.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.28 (t,J=8.8 Hz, 3H), 7.20 (dd, J=8.5, 5.9 Hz, 1H), 7.00 (dd, J=8.6, 2.3 Hz,1H), 6.93 (dd, J=9.0, 2.2 Hz, 1H), 6.81 (td, J=8.3, 2.4 Hz, 1H), 6.55(d, J=8.7 Hz, 2H), 6.29 (d, J=16.0 Hz, 1H), 3.91 (s, 3H), 3.79 (s, 3H).¹³C NMR (100 MHz, CDCl₃) δ 186.10, 167.53, 163.16 (d, J=253.1 Hz),161.27, 159.30, 148.85, 143.81, 142.73, 135.48 (d, J=3.7 Hz), 132.49 (d,J=10.6 Hz), 129.79 (d, J=9.3 Hz), 129.56, 129.36, 127.18, 126.36,124.83, 117.18 (d, J=24.9 Hz), 116.91, 116.72, 115.45, 113.83 (d, J=21.6Hz), 105.22, 55.91, 51.82.

Compounds 2-8 and 11-22 were made via an analogous procedure for thesynthesis of Compound 1 utilizing appropriate starting materials.Characterization for these compounds is shown below in Table 1.

Compound 9:5-((6-Hydroxy-2-(2-methylbenzoyl)benzo[b]thiophen-3-yl)oxy)-2-naphthoicacid

Compound 4 (100 mg, 0.21 mmol) was dissolved in 3 mL of anhydrousdichloromethane at room temperature under argon atmosphere. The solutionwas cooled using an ice water bath and BF₃.SMe₂ (1 ml, 4.2 mmol) wasadded dropwise. After stirring for 30 minutes, the solution was allowedto warm to 35° C. The reaction mixture was stirred until startingmaterial was consumed, as monitored by TLC, and then quenched bysaturated NaHCO₃/ice water. The reaction mixture was extracted withethyl acetate and washed with brine. The organic extracts were combined,dried over anhydrous Na₂SO₄, concentrated in vacuum, and purified byflash chromatography (5%-60% ethyl acetate in hexane) to afford 37 mgwhite powder (38%). ¹H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 7.93 (d,J=8.4 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.40 (d,J=8.8 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 7.28-7.08 (m, 2H), 7.01 (t, J=7.4Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.88 (dd, J=8.8, 2.1 Hz, 1H), 6.79 (s,1H), 6.74 (dd, J=8.9, 2.4 Hz, 1H), 1.95 (s, 3H). ¹³C NMR (100 MHz, MeOD)δ 192.50, 169.84, 160.87, 159.24, 150.50, 143.78, 140.65, 137.54,136.54, 132.21, 131.70, 131.42, 131.18, 130.09, 128.34, 128.08, 127.69,127.38, 127.05, 126.27, 125.78, 118.69, 117.51, 110.58, 108.92, 19.19.ESI-HRMS (m/z): [M+H]⁺ calcd. for C₂₇H₁₈O₅S: 455.0953; observed,455.0939.

Compound 10:8-((6-Hydroxy-2-(2-methylbenzoyl)benzo[b]thiophen-3-yl)oxy)quinoline-3-carboxylicacid

Compound 24 was prepared following the procedure for the synthesis ofCompound 9 to afford 33 mg (57%). ¹H NMR (400 MHz, MeOD) δ 9.20 (s, 1H),8.85 (s, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.31 (s,1H), 7.27-7.13 (m, 2H), 7.04-6.81 (m, 5H), 1.97 (s, 3H). ¹³C NMR (100MHz, MeOD with TFA vapor) δ 192.08, 165.75, 162.47, 161.00, 151.79,151.11, 149.43, 143.78, 140.53, 140.32, 136.47, 132.26, 131.43, 131.32,128.29, 127.90, 126.64, 126.32, 125.56, 124.53, 119.98, 117.75, 110.96,108.96, 19.21. ESI-HRMS (m/z): [M+H]⁺ calcd. for C₂₆H₁₇NO₅S: 456.0906;observed, 456.0893.

TABLE 1 Characterization and Biological Data of Compounds 1-24 MCF- MCF-7:5C 7WS8 IC₅₀ IC₅₀ Cmpd # Structure Name/Physical Data (nM) (nM) 1

¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 16.0 Hz, 1H), 7.37 (d, J = 9.0Hz, 1H), 7.28 (t, J = 8.8 Hz, 3H), 7.20 (dd, J = 8.5, 5.9 Hz, 1H), 7.00(dd, J = 8.6, 2.3 Hz, 1H), 6.93 (dd, J = 9.0, 2.2 Hz, 1H), 6.81 (td, J =8.3, 2.4 Hz, 1H), 6.55 (d, J = 8.7 Hz, 2H), 6.29 (d, J = 16.0 Hz, 1H),3.91 (s, 3H), 3.79 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 186.10, 167.53,163.16 (d, J = 253.1 Hz), 161.27, 159.30, 148.85, 143.81, 142.73, 135.48(d, J = 3.7 Hz), 132.49 (d, J = 10.6 Hz), 129.79 (d, J = 9.3 Hz),129.56, 129.36, 1.0 +/− 0.05 0.4 +/− 0.07 127.18, 126.36, 124.83, 117.18(d, J = 24.9 Hz), 116.91, 116.72, 115.45, 113.83 (d, J = 21.6 Hz),105.22, 55.91, 51.82. 2

(E)-3-(4-((6-Hydroxy-2-(4- hydroxybenzoyl)benzo[b]thiophen-3-yl)oxy)phenyl) acrylic acid ¹H NMR (400 MHz, MeOD) δ7.61 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 16.0 Hz, 1H), 7.43 (d, J = 8.8Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 2.1 Hz, 1H), 6.92 (dd, J= 8.8, 2.1 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 2H),6.31 (d, J = 16.0 Hz, 1H). ¹³C NMR (100 MHz, MeOD) δ 189.36, 170.39,163.61, 161.20, 160.04, 148.16, 145.39, 142.57, 132.95, 3.9 +/− 0.06(54% Emax) No Inhibition 130.77, 130.74, 130.42, 126.91, 125.84, 125.15,118.03, 117.20, 117.05, 115.87, 108.68.24 3

(E)-3-(4-((2-(2-Ethylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, MeOD) δ 7.55 (d, J = 16.0Hz, 1H), 7.42-7.26 (m, 5H), 7.24 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.7Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.88 (dd, J = 8.8, 2.1 Hz, 1H), 6.47(d, J = 8.7 Hz, 2H), 6.32 (d, J = 16.0 Hz, 1H), 2.47 (q, J = 7.6 Hz,2H), 1.02 (t, J = 7.6 Hz, 3H). ¹³C NMR (101 MHz, MeOD) δ 192.52, 170.42,160.94, 160.82, 150.26, 145.35, 143.68, 142.88, 140.37, 131.31, 130.64,130.43, 129.91, 128.29, 127.98, 126.92, 1.2 +/− 0.04 0.9 +/− 0.04126.31, 125.81, 118.08, 117.47, 116.67, 108.91, 27.10, 15.95. 4

(E)-3-(4-((2-Benzoyl-6- hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylicacid ¹H NMR (400 MHz, MeOD) δ 7.66- 7.58 (m, 2H), 7.55 (d, J = 16.0 Hz,1H), 7.50 (d, J = 7.4 Hz, 1H), 7.43-7.34 (m, 5H), 7.28 (d, J = 2.0 Hz,1H), 6.92 (dd, J = 8.8, 2.1 Hz, 1H), 6.61 (d, J = 8.8 Hz, 2H), 6.32 (d,J = 16.0 Hz, 1H). ¹³C NMR (100 MHz, MeOD) δ 190.76, 170.39, 161.08,160.51, 149.38, 145.33, 143.23, 139.90, 133.38, 130.77, 130.47, 129.70,129.13, 126.82, 125.95, 125.55, 118.13, 13 +/− 0.08 2.2 +/− 0.1 117.38,116.96, 108.75 5

(E)-3-(4-((6-Hydroxy-2-(2- methylbenzoyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, MeOD) δ 7.54 (d, J = 16.0Hz, 1H), 7.32 (dd, J = 8.7, 6.0 Hz, 3H), 7.28-7.2 (m, 3H), 7.06-7.03 (m,2H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.44 (d, J = 8.7 Hz, 2H), 6.30 (d,J = 16.0 Hz, 1H), 2.07 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ 192.43,170.39, 161.05, 160.78, 150.29, 145.35, 143.66, 140.66, 136.53, 131.49,131.22, 130.61, 130.37, 128.35, 127.64, 126.93, 126.29, 125.73, 1.3 +/−.06 0.9 +/− .09 118.02, 117.47, 116.54, 108.90, 19.32. 6

(E)-3 -(4-((2-(5-Fluoro-2- methylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, MeOD) δ 7.56 (d, J = 16.0Hz, 1H), 7.41-7.34 (m, 3H), 7.27 (d, J = 2.0 Hz, 1H), 7.10- 7.06 (m,1H), 7.02-6.93 (m, 2H), 6.89 (dd, J = 8.9, 2.1Hz, 1H), 6.53 (d, J = 8.8Hz, 2H), 6.33 (d, J = 16.0 Hz, 1H), 2.08 (s, 3H). ¹³C NMR (100 MHz,MeOD) δ 190.69, 170.37, 161.92 (d, J = 244.8 Hz), 161.03, 160.90,150.60, 145.27, 143.95, 142.21 (d, J = 6.5 Hz), 133.18 (d, 7.5 Hz),132.15 (d, 4.7 +/− 0.04 0.7 +/− 0.3 J = 3.4 Hz), 130.74, 130.62, 127.31,126.78, 125.88, 118.21, 117.63 (d, J = 21.3 Hz), 117.59, 116.48, 114.82(d, J = 23.3 Hz), 108.93, 18.48. 7

(E)-3-(4-((6-Hydroxy-2-(3- methylthiophene-2-carbonyl)benzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz,MeOD) δ 7.59- 7.51 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.7Hz, 2H), 7.26 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.90(d, J = 4.9 Hz, 1H), 6.70 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 16.0 Hz,1H), 2.23 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ 182.84, 170.46, 161.42,160.27, 148.95, 145.51, 145.27, 142.41, 136.91, 132.55, 132.20, 130.78,12.5 +/− 0.01 2.8 +/− 0.16 130.65, 126.84, 125.52, 125.14, 118.24,117.38, 117.08, 108.63, 15.66. 8

(E)-3-(4-((6-Hydroxy-2-(2- (trifluoromethyl)benzoyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, Acetone) δ 7.69(d, J = 7.9 Hz, 1H), 7.62- 7.53 (m, 2H), 7.53-7.46 (m, 4H), 7.45 (d, J =1.9 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 8.9, 2.1 Hz, 1H),6.57 (d, J = 8.8 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H). ¹³C NMR (100 MHz,Acetone) ¹³C NMR (101 MHz, CDCl₃) δ 187.60, 167.78, 160.17, 159.68,149.95, 144.51, 143.23, 139.58, 132.63, 130.73, 130.49, 130.33, 128.38,2.7 +/− 0.11 (61% Emax) 1.2 +/− 0.08 (65% Emax) 127.45, 127.24 (q, J =31.9 Hz), 127.11 (q, J = 4.6 Hz), 126.14, 125.91, 124.85 (q, J = 273.3Hz), 118.10, 117.32, 116.51, 109.12. 9

¹H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.72(d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8 8 Hz, 1H),7.30 (d, J = 1.9 Hz, 1H), 7.28- 7.08 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H),6.94 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.1 Hz, 1H), 6.79 (s, 1H),6.74 (dd, J = 8.9, 2.4 Hz, 1H), 1.95 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ192.50, 169.84, 160.87, 159.24, 150.50, 143.78, 140.65, 137.54, 136.54,132.21, 131.70, 131.42, 131.18, 130.09, 128.34, 128.08, 127.69, 127.38,127.05, 126.27, 125.78, 118.69, 117.51, 110.58, 108.92, 19.19. ESI-HRMS(m/z): [M + H]⁺ calcd. for 4.8 +/− 0.06 2.4 +/− 0.12 C₂₇H₁₈O₅S:455.0953; observed, 455.0939. 10

¹H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 8.85 (s, 1H), 7.83 (d, J = 9.0Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 7.27-7.13 (m, 2H),7.04-6.81 (m, 5H), 1.97 (s, 3H). ¹³C NMR (100 MHz, MeOD with TFA vapor)δ 192.08, 165.75, 162.47, 161.00, 151.79, 151.11, 149.43, 143.78,140.53, 140.32, 136.47, 132.26, 131.43, 131.32, 128.29, 127.90, 126.64,126.32, 125.56, 124.53, 119.98, 117.75, 110.96, 108.96, 19.21. ESI-HRMS(m/z): [M + H]⁺ calcd. for C₂₆H₁₇NO₅S: 456.0906; observed, 456.0893 32.3+/− 0.19 (52% Emax) No Inhibition 11

(E)-3-(4-((2-(2,6- Dimethylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, MeOD) δ 7.55 (d, J = 16.0Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.27-7.19 (m, 2H), 7.01 (t, J = 7.6Hz, 1H), 6.87-6.77 (m, 3H), 6.43 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 16.0Hz, 1H), 2.04 (s, 6H). ¹³C NMR (100 MHz, MeOD) δ 194.06, 170.40, 160.93,160.50, 150.47, 145.38, 143.86, 141.47, 134.76, 130.48, 130.35, 129.90,128.44, 126.74, 125.99, 117.97, 117.55, 116.38, 109.04, 19.35. 0.5 +/−0.04 0.1 +/− 0.07 12

(E)-3-(4-((2-(2,4- Dimethylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz, Acetone) δ 7.58 (d, J = 16.0Hz, 1H), 7.50- 7.38 (m, 4H), 7.25 (d, J = 7.7 Hz, 1H), 7.01 (dd, J =8.8, 2.1 Hz, 1H)), 6.96-6.86 (m, 2H), 6.57 (d, J = 8.7 Hz, 2H), 6.38 (d,J = 16.0 Hz, 1H), 2.29 (s, 3H), 2.07 (s, 3H). ¹³C NMR (100 MHz, Acetone)δ 190.44, 167.80, 160.72, 159.80, 148.66, 144.67, 142.52, 141.14,137.47, 136.47, 131.96, 130.35, 130.01, 128.72, 127.86, 126.99, 0.4 +/−0.04 0.1 +/− 0.08 126.55, 125.39, 117.81, 117.15, 116.34, 108.90, 21.31,19.33. 13

(E)-3-(4-((2-(2-Chloro-4- fluorobenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid LC-MS M/Z (M − H)⁻: 467.9 2.2 +/− 0.12 0.4+/− 0.13 14

(E)-3-(3,5-Difluoro-4-((2-(4-fluoro- 2-methylbenzoyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid LC-MS M/Z (M −H)⁻: 483.4 >10 >10 15

(E)-3-(3-Fluoro-4-((2-(4-fluoro-2- methylbenzoyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid LC-MS M/Z (M −H)⁻: 465.4 <10 <10 16

(E)-3-(4-((2-(Difluoro(4-fluoro-2- methylphenyl)methyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid LC-MS M/Z (M −H)⁻: 469.5 <100 <100 17

(E)-3-(4-((2-(1-(4-Fluoro-2- methylphenyl)cyclopropyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid LC-MS M/Z (M −H)⁻: 459.5 <100 <100 18

2-((4-((2-(4-Fluoro-2- methylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)amino)-2-oxoacetic acid ¹H NMR (400 MHz, MeOD) δ 7.46 (d,J= 8.3 Hz, 2H), 7.38-7.27 (m, 2H), 7.24 (s, 1H), 6.90-6.77 (m, 3H), 6.46(d, J = 8.2 Hz, 2H), 2.11 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ 191.26,164.87 (d, J = 248.6 Hz), 160.76, 156.78, 150.82, 143.70, 140.40 (d, J =8.6 Hz), 136.90, 136.87, 133.35, 131.10 (d, J = 9.1 Hz), 127.30, 127.03,125.84, 123.09, 118.11 (d, J = 1.7 +/− 0.07 (64% Emax) No Inhibition21.7 Hz), 117.38, 116.16, 113.05 (d, J = 21.9 Hz), 108.85, 19.46. 19

2-((4-((2-(2,4-Dimethylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)amino)-2-oxoacetic acid LC-MS M/Z (M − H)⁻: 460.1 >10 NoInhibition 20

(E)-3-(4-((2-(4-Fluoro-2,6- dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz,Acetone-d6) δ 7.60 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.44(d, J = 1.7 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.99 (dd, J = 8.8, 1.9Hz, 1H), 6.66 (d, J = 9.8 Hz, 2H), 6.60 (d, J = 8.6 Hz, 2H), 6.40 (d, J= 16.0 Hz, 1H), 2.10 (s, 6H). ¹³C NMR (100 MHz, Acetone-d6) δ 191.13,167.89, 163.21 (d, J = 244.9 Hz), 160.08, 149.15, 144.65, 142.99,137.66, 0.4 +/− 0.03 <0.1 137.58 (d, J = 8.8 Hz), 130.34, 130.13,128.63, 126.65, 125.79, 117.89, 117.34, 115.99, 114.64 (d, J = 21.5 Hz),109.12, 19.34, 19.32. 21

(E)-3-(4-((2-(4-Chloro-2,6- dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3- yl)oxy)phenyl)acrylic acid ¹H NMR (400 MHz,Acetone-d6) δ 7.60 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.45(d, J = 1.7 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.00 (dd, J = 8.8, 1.9Hz, 1H), 6.91 (s, 2H), 6.58 (d, J = 8.6 Hz, 2H), 6.40 (d, J = 16.0 Hz,1H), 2.09 (s, 6H). ¹³C NMR (100 MHz, Acetone-d6) δ 190.91, 167.77,160.17, 160.00, 149.30, 144.62, 143.07, 139.99, 136.85, 134.53, 130.26,130.17, 128.40, 127.88, 126.67, 125.82, 0.3 +/− 0.04 <0.1 117.94,117.38, 115.91, 109.13, 19.12. 22

(E)-3-(4-((6-Hydroxy-2-(2,4,6- trimethylbenzoyl)benzo[b]thiophen-3-yl)oxy)phenyl) acrylic acid ¹H NMR (400 MHz, MeOD) δ 7.55 (d, J = 15.9Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.9 Hz, 1H), 7.26 (d, J= 1.9 Hz, 1H), 6.86 (dd, J = 8.8, 2.1 Hz, 1H), 6.63 (s, 2H), 6.44 (d, J= 8.6 Hz, 2H), 6.32 (d, J = 15.9 Hz, 1H), 2.18 (s, 3H), 2.01 (s, 6H).¹³C NMR (100 MHz, MeOD) δ 194.48, 160.95, 160.62, 150.30, 145.28,143.76, 139.89, 138.64, 134.74, 130.39, 130.27, 129.13, 128.72, 126.95,125.91, 118.20, 117.55, 116.26, 109.00, 0.5 +/− 0.03 <0.1 21.13, 19.30.

ASSAYS Cell Viability of MCF7:WS8 and Cell Viability of MCF7:5C(Tamoxifen Resistant)

The DNA content of the cells was determined as previously describedusing a Fluorescent DNA Quantitation kit (cat. No. 170-2480; Bio-RadLaboratories, Hercules, Calif.). Briefly, five thousand cells wereplated per well in 96-well plates, and treatment with indicatedconcentrations of compounds was started at the same time in each well.On day 4 or 6, for MCF7:WS8 or MCF7:5C respectively, the cells in theplates were lysed and frozen at −80° C. To measure the total DNA in eachwell, the plates were allowed to warm to room temperature, incubatedwith Hoechst dye, and mixed well. The fluorescence was measured using aSynergy H4 Hybrid Multi-Mode Microplate Reader. For each analysis, sixreplicate wells were used and at least three independent experimentswere performed.

Cell Viability of 3D Spheroids

Spheroids were plated at a concentration of 1000 cells per well inCorning® 96-well clear black round-bottom ultra-low attachment spheroidmicroplate and allowed to grow in the absence of treatment for 48 hours.100 μL media was removed from each well and 100 μL 2× concentration ofthe treatment was added. This procedure was repeated every 2-3 days for12 days. Analysis occurred on day 15 after plating. CellTiter-Glo® 3DCell Viability Assay protocol was used to determine growth inhibition ofthe spheroids. The plates and reagent were allowed to warm to roomtemperature for 30 minutes. During this time, the spheroids were washedwith PBS 2 times by removing 100 μL media and replacing with PBS. 100 μLfrom each well was then removed and replaced with 100 μL CellTiter-Glo®3D reagent and spheroids were disrupted by pipetting. The plates wereplaced on a shaker for 5 minutes before allowing to equilibrate in thedark for 25 minutes. 125 μL from each well was then transferred to awhite 96-well plate before recording luminescence.

Western Blot:

Whole-cell extracts of cultured cells were prepared in lysis buffer (200mmol/L Tris, 1% Triton X-100, 5 mmol/L EDTA) with protease andphosphatase inhibitor cocktails (1:50, both from Sigma-Aldrich) afterscraping from the culture plates. Protein concentration was measuredusing the Bradford method (Bio-Rad). Proteins were separated underdenaturing conditions and blotted onto nitrocellulose membrane (Bio-Rad)using a wet transfer system (Bio-Rad). Images of blots were acquired ona Bio-Rad ChemiDoc System following incubation with Super Signal WestDura luminol solution (Thermo Fisher Scientific).

The results of the foregoing are shown in FIGS. 1-4 and Table 2.

TABLE 2 IC₅₀ of ER downregulation from in-cell western blot experimentsCompound IC₅₀ (nM) 1 0.7 3 1.2 4 5.0 5 1.1 6 1.1 7 4.6

A selection of compounds of the current invention were furthercharacterized by their estrogen receptor degradation, estrogen receptorbinding efficacy, and inhibition of 3D spheroid growth.

TABLE 3 ERα degradation, antagonism of E₂ signaling, ERα relativebinding affinity, and inhibition of growth of ER+ cells cultured in 3Dspheroids % growth of MCF-7:ws8 ERα ICW ERE 3D spheroids ERα RBA % EC₅₀luciferase (rel. to binding Ki (relative to Compounds R₁ (nM)^(a) IC₅₀(nM)^(b) vehicle)^(c) (nM)^(d) E₂)^(e) GDN-0810  0.8 ± 0.07 11.1 ± 0.14 15 ± 3.00 0.37 ± 0.1 53.4 ± 15.0  5

 1.1 ± 0.05 16.7 ± 0.07  12 ± 0.02 1.29 ± 0.4 15.5 ± 4.2   1

0.71 ± 0.05  8.8 ± 0.11 3.3 ± 0.01 0.65 ± 0.2 30.6 ± 8.7  12

0.92 ± 0.05  4.5 ± 0.07  12 ± 0.01 0.50 ± 0.1 40.3 ± 4.8  11

0.65 ± 0.06  4.2 ± 0.05  14 ± 1.00  2.0 ± 0.2 9.8 ± 0.7 21

0.07 ± 0.13  2.4 ± 0.10 1.3 ± 0.01 0.57 ± 0.1 34.8 ± 6.2  20

0.24 ± 0.16  3.1 ± 0.07 2.1 ± 0.01 0.73 ± 0.2 27.5 ± 7.0  ^(a)Potencyfor induction of ER degradation measured at 10 concentrations usingin-cell westerns (ICW). ^(b)Potency of antagonism of ERE-luciferasereporter. ^(c)Spheroid growth inhibition after SERD treatment (100 nM)expressed as % of growth of DMSO vehicle control. Data show mean ands.e.m. ^(d)Binding affinities calculated by the formula: Ki =(Kd/[estradiol]/RBA) * 100, where the Kd for estradiol is 0.2 nM.^(e)Relative binding affinity (RBA) values, determined by radioliganddisplacement assays expressed as IC₅₀ estradiol/IC₅₀ compound × 100(RBA, estradiol = 100%).

Mouse PK and Animal Data

The plasma concentrations of Compounds 1, 5, 11, 12, 20, and 21, at 0.5hours and 4 hours (100 mg/kg in a 0.5% CMC suspension p.o.) weremeasured to select a BT-SERD for study in an ectopic xenograft mousemodel of endocrine-resistant ER+ breast cancer (Table 4). The oralbioavailability of Compounds 20 and 21 were further studied by measuringplasma concentrations at multiple time points. The MCF-7:TAM1 xenograftmodel was allowed to proceed for 5.5 weeks prior to treatment and wasrandomized to six treatment groups with an average tumor area of 0.325cm². Tamoxifen (100 mg/kg) was entirely without effect, demonstratingthe anticipated resistance of this tumorigenic TR breast cancer cellline to tamoxifen. GDN-0810 at a dose of 100 mg/kg, used previously inthe literature, caused regression of tumor size by 21% at day 23 aftertreatment. Compound 12 (100 mg/kg) also caused tumor regression similarto GDN-0810 (26.7% in tumor area reduction at day 20), whereas Compound21 showed the best efficacy in tumor regression (49% reduction) at adose of 100 mg/kg. Regression was dose-dependent for Compound 21: at 30mg/kg average tumor area was reduced 27%. Injection of tumorigenic cellsinto mammary fat pads of nude mice produces distinct mammary tumorsallowing assessment of individual tumor response, again demonstratingthe efficacy of SERD Compound 21. No weight loss was observed during thecourse of the animal study.

TABLE 4 Plasma concentration of benzothiophene analogs after oraladministration Compound/ Time 1 (nM) 11 (nM) 12 (nM) 5 (nM) 21 (nM) 20(nM) 0.5 h 1238 1006 3874 5575 10183 9723   4 h  145 0.5  432  47  858 164 ^(a)All compounds administered by oral gavage at 100 mg/kg inPEG400/PVP/TW80/CMC in water, 9:0.5:0.5:90. Data was the average plasmaconcentration of three mice at 0.5 h and 4 h.

Animal Experiments

MCF-7: Tam1 tumors were grown in 4-6 week old ovariectomized athymicnude mice (Harlan Laboratories) and E2 was administered via silasticcapsules (1.0 cm) implanted subcutaneously between the scapulae aspreviously described. The compound was administered at a dose of 100mg/kg or 30 mg/kg daily for 3.5 weeks in a formulation of 0.5% CMC:PEG-400: Tween-80: PVP (90:9:05:0.5) solution. Tumor cross-sectionalarea was determined weekly using Vernier calipers and calculated usingthe formula (length/2)×(width/2)×π. Mean tumor area was plotted againsttime (in weeks) to monitor tumor growth.

Cell Lines and Culture Conditions

MCF-7:WS8 is hormone-dependent human breast cancer cell clonesmaintained in phenol red containing RPMI-1640 medium supplemented with10% FBS at 37° C., 5% CO₂ that have been previously described. MCF-7:5Ccells were maintained in phenol-red free RPMI 1640 medium supplementedwith 10% charcoal-dextran treated fetal bovine serum at 37° C., 5% CO₂as previously described. The MCF-7:5C cells served as AI resistant cellsand were generated from MCF-7:WS8 cells by long-term estrogendeprivation.

Cell Growth Assay

Cells were grown in phenol red-free media for 2 days prior to eachexperiment. On the day of the experiment, cells were seeded in 96-wellplate at a density of 5000 cells/well and treated with either 0.1% (v/v)DMSO, 1 nM E2, or compounds prepared in phenol red free media. Allcompounds were dissolved in DMSO and added to the medium at a final1:1000 dilution. DNA content was determined on Day 5 (WS8) or Day 6 (5C)by Hoechst 33258 dye. Fluorescence signals were read by the Synergy H4(BioTek).

In-Cell Western Analysis

MCF-7:WS8 cells were kept in stripped medium 2 days, and 2.0×104/well ofthe cells were plated in clear bottom 96-well black plates for 48 hoursprior to addition of compounds for 24 hours. Fixation, detection of ESR1(sc-8002) and analysis were performed per LI-COR manufacturer's protocolusing the In-Cell Western™ Assay Kits and LI-COR ODYSSEY infra-redimaging system. Data was normalized to CellTag 700 stain.

3D-Spheroid Growth Assay

Spheroids were plated at 1000 cells/well in Corning® 96-well black clearround-bottom, ultra-low attachment spheroid microplates and grown in theabsence of treatment for 24 hours. Spheroids were then treated with 2×treatment media following the removal of 100 μL media from each well.Treatment was repeated every 2-3 days for 14 days. CellTiter-Glo® 3DCell Viability Assay protocol was used to determine growth inhibition ofthe spheroids. On day 15, spheroid plates and reagent (CellTiter-Glo® 3DReagent) were allowed to come to room temperature for 30 minutes. Duringthis time, the spheroids were washed with PBS by removing 100 μL mediaand replacing with PBS. 100 μL from each well was then removed andreplaced with 100 μL of the reagent and spheroids were disrupted bypipetting. The plates were then placed on a shaker for 5 minutes beforeequilibrating in dark for 25 minutes. 125 μL from each well was thentransferred to a white 96-well plate before recording luminescence usingan empty well for the background reading.

Binding Affinity Studies

Binding affinities were also determined by a competitive radiometricbinding assay using 2 nM [³H]estradiol as tracer (PerkinElmer, Waltham,Mass.) and full-length purified human ERα (Pan Vera/Invitrogen,Carlsbad, Calif.), as reported previously. The RBA values werecalculated using the following equation: IC₅₀ estradiol/IC₅₀compound×100.

Estrogen Response Elements (ERE) Luciferase Assay in MCF-7 Cells.

MCF-7:WS8 cells were kept in stripped medium 3 days prior to treatment.Cells were plated at a density of 2×10⁴ cells/well in 96-well plates andwere co-transfected with 5 μg of the pERE-luciferase plasmid per plate,which contained three copies of the Xenopus laevis vitellogenin A2 EREupstream of firefly luciferase and 0.5 μg of pRL-TK plasmid (Promega,Madison, Wis.) containing a cDNA encoding Renilla luciferase.Transfection was performed for 6 hours using the Lipofectamine 2000transfection reagent (Invitrogen) in Opti-MEM medium according to themanufacturer's instructions. Cells were treated with test compoundsafter 6 hours, and the luciferase activity was measured after 18 hoursof treatment using the dual luciferase assay system (Promega) withSynergy H₄ (Bio Tek).

This specification has been described with reference to embodiments ofthe invention. However, one of ordinary skill in the art will appreciatethat various modifications and changes can be made without departingfrom the scope of the invention as set forth in the claims below. Whileonly certain representative materials, methods, and aspects of thesematerials and methods are specifically described, other materials andmethods and combinations of various features of the materials andmethods are intended to fall within the scope of the appended claims, asif specifically recited. Accordingly, the specification is to beregarded in an illustrative rather than a restrictive sense, and allsuch modifications are intended to be included within the scope ofinvention.

We claim:
 1. A compound of formula:

or a pharmaceutically acceptable salt thereof; wherein: m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, or 4; X_(B) is selected from —O—, —CH₂−, —S—,—NH—, —NMe-, —CF₂—, and —C₃cycloalkyl-; Y is —CF₂— or —C₃cycloalkyl-;Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclicheteroaryl or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl; Ring C isphenyl, thiophenyl, 5- or 6-membered monocyclic heteroaryl, or 7-, 8-,9- or 10-membered bicyclic heterocyclyl; R₁ is selected from hydroxyl,hydrogen, halogen, —O(C₁-C₆ alkyl), —OC(O)(C₁-C₆ alkyl), —OC(O)C₆H₅,—OC(O)O(C₁-C₆ alkyl), —OC(O)OC₆H₅ and —OSO₂(C₂-C₆ alkyl); R₂ is selectedfrom —CH═CHCOOH, —NH(CO)COOH, —COOH, —C₂-C₆alkenylene-COOH, and—C₂-C₆alkynylene-COOH; R₃ is independently selected at each occurrencefrom hydrogen, halogen, —CN, NO₂, —C₁-C₆alkyl, and —C₁-C₆fluoroalkyl;and R₄ is independently selected at each occurrence from hydrogen,halogen, hydroxyl, —C₁-C₆alkyl, —C₁-C₆fluoroalkyl, —CN, —O(C₁-C₆ alkyl),and —O(C₁-C₆fluoroalkyl).
 2. The compound of claim 1, wherein X_(B) is—O—.
 3. The compound of claim 2, wherein Y is —CF₂—.
 4. The compound ofclaim 2, wherein Y is —C₃cycloalkyl-.
 5. The compound of claim 2,wherein Ring B is phenyl.
 6. The compound of claim 2, wherein Ring C isphenyl.
 7. The compound of claim 2, wherein R₁ is hydroxyl.
 8. Thecompound of claim 7, wherein R₂ is —CH═CHCOOH.
 9. The compound of claim8, wherein R₃ is hydrogen.
 10. The compound of claim 9, wherein R₄ isindependently selected at each occurrence from halogen and —C₁-C₆alkyl.11. The compound of claim 10, wherein m is
 0. 12. The compound of claim11, wherein n is
 3. 13. The compound of claim 1, wherein the compound isof Formula:

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, wherein the compound is:

or a pharmaceutically acceptable salt or prodrug thereof.
 15. Thecompound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt or prodrug thereof.
 16. Thecompound of claim 1, wherein the compound is:

a pharmaceutically acceptable salt thereof.
 17. The compound of claim 1,wherein the compound is:

a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 19.A method of treating an estrogen receptor positive breast cancer in ahuman comprising administering to the human an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof. 20.The method of claim 19, wherein the estrogen receptor positive breastcancer is metastatic.